Prepared in collaboration with the WHO Collaborating Centre for International Drug Monitoring,

Uppsala, Sweden

TheThe aim aim of of the the Newsletter Newsletter is is to to No.No. 2 3, ,201 20142

disseminatedisseminate information information on on the the safetysafety and and efficacy efficacy of of

pharmaceuticalpharmaceutical products, products, based on communications received based on communications received from our network of "drug from our network of "drug information officers" and other information officers" and other TheThe WHO WHO Pharmaceutical Pharmaceuticalss Newsletter Newsletter provides provides you you with with sources such as specialized sources such as specialized thethe latest latest information information on on the the safety safety of of medicines medicines and and bulletins and journals, as well as bulletins and journals, as well as legallegal actions actions taken taken by by regulatory regulatory authorities authorities across across the the partners in WHO. The information partners in WHO. The information world.world. It It also also provides provides signals signals from from the the Uppsala Uppsala is produced in the form of résumés is produced in the form of résumés MonitoringMonitoring Centre's Centre's SIGNAL SIGNAL document document. in English, full texts of which may in English, full texts of which may be obtained on request from: be obtained on request from: Safety and Vigilance, The feature article in this issue gives you…

Quality Assurance EMPand Safety:-HIS, World Health Organization, Medicines, EMP-HSS, 1211 Geneva 27, Switzerland, E-mailWorld address: Health [email protected] Organization,

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TABLE OF CONTENTS

Regulatory Matters Aliskiren, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers ...... 4 Azathioprine and mercaptopurine ...... 4 Cetuximab ...... 4 Combined hormonal contraceptives ...... 5 Diacerein-containing medicines ...... 5 Doripenem ...... 5 Lithium ...... 5 Methysergide-containing medicines ...... 6 Orlistat ...... 6 Quetiapine ...... 7 Strontium ranelate ...... 7 Safety of medicines Saxagliptin ...... 8 St John’s wort and hormonal contraceptives, including implants ...... 8 Testosterone Products ...... 8 Signal Combined Citalopram and Ramipril treatment - Hyponatraemia ...... 10 Combined and treatment - Acute renal failure ...... 13 Tocilizumab – Psoriasis and Aggravated psoriasis ...... 16 Vemurafenib and Pancreatitis ...... 23

WHO Pharmaceuticals Newsletter No. 2, 2014  3

REGULATORY MATTERS

Azathioprine and overall survival, progression- Aliskiren, free survival, and objective mercaptopurine response rates have been angiotensin- shown in people with RAS converting enzyme Association with mutations (at exons 2, 3, and inhibitors or Hepatosplenic T-Cell 4 of KRAS and NRAS) who Lymphoma received cetuximab (Erbitux®) angiotensin receptor Canada. Triton Pharma Inc. in combination with FOLFOX4 blockers and Teva Canada Ltd., in (oxaliplatin-containing) consultation with Health chemotherapy versus FOLFOX4 New warnings regarding Canada, informed the alone. Cetuximab is now blood pressure drugs association between the use of indicated for the treatment of people with epidermal growth Canada. Health Canada purine antagonists azathioprine (Imuran®) or mercaptopurine factor receptor (EGFR)- informed health-care expressing, RAS wild-type professionals and patients of (Purinethol®) and the development of hepatosplenic metastatic colorectal cancer in the risks associated with combination with irinotecan or combining more than one of T-cell lymphoma (HSTCL), a rare, aggressive and often fatal oxaliplatin based the following blood pressure chemotherapy or as a single medicines: aliskiren (renin cancer, mostly in patients where it is used for agent. Evidence of wild type inhibitor), angiotensin- RAS status at these exons is converting enzyme inhibitors inflammatory bowel disease (IBD). Azathioprine is a drug required before initiating (ACEIs) or angiotensin treatment with cetuximab receptor blockers (ARBs). used to treat adult rheumatoid arthritis and help prevent alone or in combination with Recent studies demonstrated chemotherapy in metastatic that any combination of kidney transplant rejection. Mercaptopurine is a drug colorectal cancer. Cetuximab aliskiren, ACEIs or ARBs combined with oxaliplatin- increases the risks of approved to treat leukemias. Azathioprine or containing chemotherapy is hypotension, hyperkalemia and now contraindicated in people kidney problems. mercaptopurine monotherapies are not authorized by Health with metastatic colorectal Furthermore, aliskiren should Canada for the treatment of cancer who have mutant RAS not be taken in combination IBD. at these exons or unknown with ACEIs or with ARBs in RAS status. Cetuximab patients with diabetes or Azathioprine and (Erbitux®) is a treatment for kidney disease due to the mercaptopurine labels were people with metastatic additional risks of stroke and updated for HSTCL and colorectal cancer. physicians should discuss the syncope in these patients. The It is also advised that RAS product labels have been currently available information regarding risks and benefits of mutation status should be updated to better reflect the determined by an experienced new recommendations these treatments with their patients. laboratory using a validated regarding the safe use of these test method. Prescribing medicines. Reference: information for cetuximab in (See WHO Pharmaceuticals Advisories, Warnings and the treatment of people with Newsletter No.3, 2012 for new Recalls, Health Canada, 27 squamous-cell carcinoma of warning and contraindication in March 2014 (www.hc- the head and neck is not the US, No.1, 2012 for contra- sc.gc.ca). changed by the new indication in patients with information from this analysis. diabetes taking an ACE Cetuximab Reference: inhibitor or an ARB in Canada Drug Safety Update, February and No.2, 2012 in Europe). 2014, Volume 7, issue 7, A1 Importance of MHRA, (www.mhra.gov.uk). Reference: establishing wild type Advisories, Warnings and RAS (KRAS and NRAS) Recalls, Health Canada, 4 February 2014 (www.hc- status before treatment sc.gc.ca). of metastatic colorectal cancer UK. The Medicines and Healthcare products Regulatory Agency (MHRA) announced that, in the treatment of metastatic colorectal cancer, inferior WHO Pharmaceuticals Newsletter No. 2, 2014  4

REGULATORY MATTERS

Combined hormonal Diacerein-containing Reference: Press release, EMA, 21 March contraceptives medicines 2013 (www.ema.europa.eu).

Review confirms risk of Recommendations to venous restrict the use of Doripenem thromboembolism is diacerein-containing small medicines Risk when used to treat UK. The MHRA announced that Europe. The Co-ordination pneumonia on ventilated a review of the latest evidence Group for Mutual Recognition patients on the risk of and Decentralised Procedures USA. The U.S. Food and Drug thromboembolism in – Human (CMDh) endorsed Administration (FDA) association with combined recommendations to restrict concluded that doripenem hormonal contraceptives the use of diacerein-containing (Doribax®), an antibacterial (CHCs) concluded that: medicines in order to manage drug used to treat patients the risks of severe diarrhoea - the risk of blood clots with all who develop pneumonia while and effects on the liver. Due to low-dose CHCs is small on ventilators, carries an the risks associated with - there is good evidence that increased risk of death and severe diarrhoea, diacerein is the risk of venous lower clinical cure rates no longer recommended in thromboembolism (VTE) may compared to use of imipenem patients aged 65 years and vary between products, and cilastatin for injection above. It is also advised that depending on the progestogen (Primaxin®). Doripenem is not patients start treatment on - CHCs that contain approved to treat any type of half the normal dose (i.e. 50 levonorgestrel, norethisterone, pneumonia. mg daily instead of 100 mg) or norgestimate have the and should stop taking Health-care professionals lowest risk of VTE diacerein if diarrhoea occurs. should consider whether the - the benefits of any CHC far benefits of doripenem outweigh the risk of serious In addition, diacerein- treatment are likely to exceed side effects containing medicines must not its potential risks in patients - prescribers and women be used in any patient with who develop pneumonia while should be aware of the major liver disease or a history of on ventilators. Doripenem is risk factors for liver disease, and doctors still considered safe and thromboembolism, and of the should be monitoring their effective for its FDA-approved key signs and symptoms patients for early signs of liver indications - treatment of problems. Doctors should also Health-care professionals are adults with complicated intra- note that, based on available advised to consider such abdominal infections and data, the use of diacerein is to factors and remain vigilant for complicated urinary tract be limited to treating signs & symptoms. infections, including kidney symptoms of infections (pyelonephritis). affecting the hip or knee. Health-care professionals are Treatment should only be (See WHO Pharmaceuticals also advised to remind women started by doctors experienced Newsletters No. 2, 2012 for to read the Patient Information in treating osteoarthritis. higher mortality rate and a Leaflet that accompanies each lower clinical cure rate pack of CHCs, to read the These recommendations are observed during a comparative information provided in user based on the review of the clinical trial in Canada) card and information sheet and benefits and risks of diacerein to mention that they are using conducted by the EMA’s References: a CHC if asked whether they Pharmacovigilance and Risk FDA Drug Safety are taking any medicines. Assessment Committee (PRAC) Communication, US FDA 5 and follow concerns raised by March 2014 (www.fda.gov). Reference: the French medicines agency Drug Safety Update, February (ANSM) about diacerein’s 2014, Volume 7, issue 7, A2 gastro-intestinal and liver Lithium MHRA, (www.mhra.gov.uk). effects. Risk of hypercalcemia Diacerein is a slow-acting and hyperparathyroidism medicine of the class ‘’ used to treat Canada. Health Canada joint diseases such as informed health-care osteoarthritis. professionals that it has reviewed the available evidence and scientific

WHO Pharmaceuticals Newsletter No. 2, 2014  5

REGULATORY MATTERS literature, and determined that In addition, treatment should Orlistat lithium therapy can cause only be started and supervised hypercalcemia which may or by a specialist doctor with Interaction with may not be accompanied with experience in treating migraine hyperparathyroidism. The and cluster headaches. antiretroviral HIV benefits of this drug in the Patients should also be medicines treatment of bipolar disorder screened for fibrosis at the UK. The MHRA announced that continue to outweigh the start of treatment and should orlistat may theoretically known risks of this drug. have additional screenings reduce the absorption of every 6 months. Treatment antiretroviral HIV medicines. Lithium is used in the must be discontinued if This may be due to retention treatment of manic episodes of symptoms of fibrosis occur. of lipophilic medicines in the manic-depressive illness. It is or used to treat acute manic The Agency’s Committee for reduced gastrointestinal tract episodes, and as a long-term Medicinal Products for Human transit time. This interaction therapy to reduce their Use (CHMP), which conducted could negatively affect the frequency and severity. the review, noted that these efficacy of antiretroviral HIV recommendations were Health Canada recommends medications. Reports have necessary due to the reports of health-care professionals to been received of suspected fibrosis seen with consider calcium blood levels interactions between orlistat methysergide and other before starting a patient on and efavirenz, and between medicines of the same class lithium treatment, again six orlistat and lopinavir. However, (ergot derivatives). The months after initiation of the the theoretical interaction symptoms of fibrosis often drug, and on an annual basis mechanism described above take some time to appear and after that, in long-term could also apply to other without screening, the treatment. It is also antiretroviral medicines. diagnosis may come too late to recommended to consider prevent severe (and potentially Health-care professionals are measuring parathormone blood life-threatening) damage to advised to initiate orlistat level to identify or rule out organs . treatment only after careful hyperparathyroidism if consideration of the possible necessary. The Committee noted that impact on efficacy of there is some evidence of a Reference: antiretroviral HIV medicines. clinically relevant effect of Advisories, Warnings and Pharmacists should advise methysergide when used for Recalls, Health Canada, 5 people who take antiretroviral prevention in patients who February 2014 (www.hc- HIV medicines to consult their regularly get migraines and sc.gc.ca). doctor before taking non- cluster headaches and for prescription 60 mg orlistat whom treatment options are Methysergide- limited. Methysergide has also Orlistat is a potent, specific, been used for treating and long-acting inhibitor of containing diarrhoea caused by carcinoid gastrointestinal lipases which medicines disease. However, there were decreases the amount of fat no data to support this use and absorbed from the diet. New recommendations methysergide should therefore Orlistat is indicated for weight no longer be used in carcinoid follow concerns over loss in combination with a low- disease. calorie, low-fat diet. It is association with fibrosis available as 120 mg capsules Methysergide is a medicine Europe. The EMA under the brand name that belongs to the class ‘ergot recommended restricting the Xenical® and as 60 mg alkaloids’ that has been used use of methysergide due to capsules under the brand in the EU for preventing concerns that it could cause name Alli™. Xenical is only migraines (with or without fibrosis, a condition in which available with a prescription, aura) and other types of fibrous tissue accumulates in whereas Alli™ is available throbbing headaches. the body’s organs potentially without a prescription under Reference: damaging them. Methysergide the supervision of a Press release, EMA, medicines are now only to be pharmacist. used for preventing severe 21 February 2013 intractable migraines and (www.ema.europa.eu). Reference: cluster headaches when Drug Safety Update, March standard medicines have 2014, Volume 7, issue 8, A1 failed. MHRA, (www.mhra.gov.uk).

WHO Pharmaceuticals Newsletter No. 2, 2014  6

REGULATORY MATTERS

Quetiapine information regarding QT of heart and circulatory prolongation, VTE, akathisia problems and limiting its use and neutropenia in the to those who cannot take other Risk of QT prolongation precautions section. medicines approved for the Australia. The Therapeutic treatment of osteoporosis. In Reference: Goods Administration (TGA) addition, patients treated with Medicines Safety Update Vol 5, advised health-care strontium ranelate should be No. 1, February 2014. professionals that the Product screened and monitored (www.tga.gov.au). Information (PI) for quetiapine regularly, every 6 to 12 (Seroquel® and generics) was months. updated to include additional information regarding risks of Strontium ranelate Additional risk minimisation QT prolongation. Quetiapine is measures include providing an atypical antipsychotic drug Remain available but educational material to indicated for the treatment of with further restrictions prescribers to ensure that only the appropriate patients are schizophrenia and bipolar Europe. The EMA concluded treated with the medicine. disorder. its review of strontium ranelate Importantly, the company is (Protelos® and Osseor®) and The PI for quetiapine products required to conduct further recommended further now advises, particularly in research to demonstrate the restricting the use of the elderly patients, to avoid effectiveness of the new medicine to patients who concomitant treatment with measures. antipsychotics and other drugs cannot be treated with other that are known to prolong the medicines approved for Strontium ranelate is QT interval. These include: osteoporosis. In addition these authorised in the EU to treat patients should continue to be severe osteoporosis in women • Class IA antiarrhythmics evaluated regularly by their who have been through (such as disopyramide) doctor and treatment should menopause and who are at • Class III antiarrhythmics be stopped if patients develop high risk of fracture to reduce (such as amiodarone and heart or circulatory problems, the risk of fractures’ of the sotalol) such as uncontrolled high spine and the hip. It is also blood pressure or angina. As used to treat severe • antipsychotics (such as recommended in a previous osteoporosis in men who are at ziprasidone, chlorpromazine review, patients who have a high risk of fracture. and haloperidol) history of certain heart or Reference: circulatory problems, such as • antibiotics (such as Press release, EMA, stroke and heart attack, must erythromycin) 21 February 2013 not use the medicine. (www.ema.europa.eu). • others (such as These final recommendations citalopram, pentamidine and from the Agency’s Committee methadone). for Medicinal Products for The updated information also Human Use (CHMP) come after advises that quetiapine should initial advice from the be avoided in circumstances Pharmacovigilance Risk that may increase the risk of Assessment Committee (PRAC) torsades de pointes and/or to suspend the medicine due to sudden death, including a its cardiovascular risk. history of cardiac arrhythmias, The CHMP noted that study hypokalaemia or data showed a beneficial effect hypomagnesaemia, and in preventing fractures, congenital prolongation of the including in patients at high QT interval. risk of fracture. In addition, Additionally, the PI has also available data do not show been updated to include evidence of an increased further information about the cardiovascular risk with risk of venous strontium ranelate in patients thromboembolism (VTE), who did not have a history of akathisia, neutropenia. heart or circulatory problems. The CHMP considered that the Health-care professionals are cardiovascular risk in patients encouraged to review the taking strontium ranelate can latest PI for quetiapine and be managed by restricting its particularly the updated use to patients with no history WHO Pharmaceuticals Newsletter No. 2, 2014  7

SAFETY OF MEDICINES

St John’s wort and contraceptives except Saxagliptin intrauterine devices, for which hormonal there are currently no data. It contraceptives, is also advised to encourage Review heart failure risk including implants women to read the Patient USA. The US FDA requested Information Leaflet that comes clinical trial data from the with their hormonal Reduced contraceptive manufacturer of saxagliptin contraceptive. (Onglyza® and Kombiglyze™ effect XR) to investigate a possible UK. The Medicines and Reference: association between use of the Healthcare products Drug Safety Update, March type 2 diabetes drug and heart Regulatory Agency (MHRA) 2014, Volume 7, issue 8, A2 failure. The US FDA’s request announced that St John’s wort MHRA, (www.mhra.gov.uk). resulted from a study interacts with hormonal published in the New England contraceptives. This interaction Testosterone Journal of Medicine (NEJM), reduces the effectiveness of which reported an increased these contraceptives and Products rate of hospitalization for heart increases the risk of unplanned failure, when the heart does pregnancy. This applies to all Investigating risk of not pump blood well enough, hormonal contraceptives cardiovascular events with use of saxagliptin except intrauterine devices, for USA. The US FDA is compared to an inactive which there are currently no investigating the risk of stroke, treatment. The study did not data heart attack, and death in men find increased rates of death or St John’s wort (Hypericum taking FDA-approved other major cardiovascular perforatum L.) is a herbal testosterone products. The US risks, including heart attack or medicine traditionally used to FDA is monitoring this risk and stroke, in patients who relieve slightly low mood and decided to reassess this safety received saxagliptin. The mild anxiety. issue based on the recent manufacturer is expected to publication of two separate submit the trial data to FDA by The MHRA received two Yellow studies that each suggested an early March 2014, after which Card reports in the last quarter increased risk of cardiovascular FDA will conduct a thorough of 2013 of suspected events among groups of men analysis and report findings interactions in women with prescribed testosterone publicly. implanted contraceptives therapy. The US FDA provided containing etonogestrel At this time, the US FDA this alert while it continues to (Nexplanon® and considered information from evaluate the information from Implanon®). These women the NEJM study to be these studies and other started taking St John’s wort preliminary. Analysis of the available data. The US FDA will and then had unplanned saxagliptin clinical trial data is communicate final conclusions pregnancies. part of a broader evaluation of and recommendations when all type 2 diabetes drug There are warnings about the evaluation is complete. therapies and cardiovascular these interactions and their Testosterone is a hormone risk. consequences in the product essential to the development information provided with all Saxagliptin is used along with of male growth and masculine contraceptives and the diet and exercise to lower characteristics. Testosterone authorised St John’s wort blood sugar in adults with type products are FDA-approved products. Some unlicensed 2 diabetes. It works by only for use in men who lack products on the UK market or increasing the amount of or have low testosterone levels available online do not include insulin produced by the body in conjunction with an the appropriate warnings after meals, when blood sugar associated medical condition. regarding possible interactions. is high. The lack of warnings does not At this time, the FDA has not It is recommended that mean these products do not concluded that FDA-approved patients should not stop taking interact with other products. testosterone treatment saxagliptin and should speak increases the risk of stroke, Health-care professionals are with their health-care heart attack, or death. The US recommended to advise professionals about any FDA advised that patients women taking hormonal questions or concerns. should not stop taking contraception for pregnancy prescribed testosterone References: prevention that they should products without first FDA Drug Safety not take herbal products that discussing any questions or Communication, US FDA 11 contain St John’s wort. This concerns with their health-care February 2014 (www.fda.gov). applies to all hormonal WHO Pharmaceuticals Newsletter No. 2, 2014  8

SAFETY OF MEDICINES professionals. Health-care professionals should consider whether the benefits of FDA- approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed. References: FDA Drug Safety Communication, US FDA 31 January 2014 (www.fda.gov).

WHO Pharmaceuticals Newsletter No. 2, 2014  9

SIGNAL

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

The signals in this Newsletter are based on information derived from Individual Case Safety Reports (ICSRs) available in the WHO Global ICSR Database, VigiBase®. The database contains over 8 million reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO Programme for International Drug Monitoring. VigiBase is, on behalf of the WHO, maintained by the Uppsala Monitoring Centre (UMC) and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection process. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC Caveat document available on page 29. For information on the UMC Measures of Disproportionate Reporting please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2014.

UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific research within the field of pharmacovigilance. UMC’s vision is to improve worldwide patient safety and welfare by reducing the risk of medicines. For more information, visit www.who-umc.org. To leave a comment regarding the signals in this Newsletter, please contact: the Uppsala Monitoring Centre, Box 1051, SE-751 40 Uppsala, Sweden. E-mail: [email protected].

Combined Citalopram and Ramipril treatment - Hyponatraemia Prof. Staffan Hägg, Sweden

Summary anticancer drugs, antipsychotics and selective serotonin reuptake inhibitors (SSRIs) including Hyponatraemia is a recognized adverse drug 1-4 reaction for both citalopram and ramipril even if citalopram. The incidence of SSRI induced hyponatraemia has been reported as varying the documentation for the latter drug is very 3 limited. As of 5 May 2013 there were 56 Individual between 0.5% and 32%. Also angiotensin con- verting enzyme (ACE) inhibitors have been found Case Safety Reports (ICSRs) of hyponatraemia in 3,5 association with the combination ramipril and to cause hyponatraemia infrequently. Izzedine citalopram in the WHO Global ICSR Database, et al. summarized 17 cases of severe hyponatraemia induced by ACE inhibitors VigiBase®. Although not described in the literature 5 a drug interaction between citalopram and ramipril previously reported in the literature. In 10 of is consistent with known pharmacological these cases hyponatraemia occurred in patients properties of the drugs and individuals taking receiving combination diuretic therapy. multiple drugs known to cause hyponatraemia is The risk of drug induced hyponatraemia is highest at increased risk. An association is further during the first weeks of treatment1 and higher in supported by a plausible time course in some of elderly people than in younger people.1-3 Patients the ICSRs in VigiBase. This possible effect is receiving multiple medications known to cause probably drug class related rather than substance hyponatraemia (most often diuretics) are also at related and the association should be evaluated increased risk.3,6,7 Other important risk factors for further. hyponatraemia are low body mass index (BMI), low basal levels of hyponatraemia, and female Introduction sex.1-4 Hyponatraemia is a common and sometimes The mechanism by which SSRIs cause serious electrolyte imbalance ascribed to either hyponatraemia is mainly through SIADH.1,6,7 The water retention (most frequent) or loss of effective mechanism by which ACE inhibitors induce solute (sodium and potassium) in excess of hyponatraemia is not completely understood but is 1-4 water. Water retention is most often caused by probably related to the fact that ACE inhibitors can the syndrome of inappropriate antidiuretic block the conversion of angiotensin I to 4 hormone (SIADH). Common causes of angiotensin II in the peripheral circulation but not hyponatraemia are malignancy, pulmonary in the brain.3,5 This can lead to an increased disorders, central nervous system (CNS) disorders amount of circulating angiotensin I which can and medications such as diuretics, antiepileptics, enter the brain where it is converted to non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II. Angiotensin II may stimulate thirst

WHO Pharmaceuticals Newsletter No. 2, 2014  10

SIGNAL and release antidiuretic hormone (ADH) from the time to onset (from the first day of treatment with hypothalamus, eventually leading to both drugs) could be calculated in nine of these: hyponatraemia. one day (two cases), three days (four cases), two weeks (two cases) and nine months (one case). In Reports in VigiBase one case, ramipril was started 18 days after citalopram, with a time to onset of 11 days. Fifty-six Individual Case Safety Reports (ICSRs) of Another three patients had been treated with both hyponatraemia during treatment with citalopram of the drugs together, from unknown dates when and ramipril have been entered into the WHO the onset of reaction occurred. In two cases the Global ICSR Database, VigiBase® since 2001 (as combination treatment was started after onset of of 5 May 2013). Both of the drugs were reported hyponatraemia. as interacting, suspected and/or concomitant. Seven of the ICSRs are duplicates, which leaves Both citalopram and ramipril were reported 49 cases for assessment. together as interacting in three cases. In four additional cases, where both drugs were reported Citalopram and ramipril were reported together as as suspected, the WHO-ART terms “drug either interacting or suspected in 18 cases, which interaction” or “drug interaction potentiation” were should be compared to an expected 3.4. The reported. In one case citalopram was reported as omega value for these 18 cases is 2.44 with a interacting and ramipril as suspected, and in lower credibility interval limit of 1.76, which another case ramipril was reported as interacting indicates a statistically significant association while citalopram was reported as concomitant. between the combination treatment and the suspected adverse drug reaction (ADR). Co-medication was reported for all patients. In 24 cases there were other co-suspected and/or Examining the number of reports submitted in interacting drugs. Thirty-two patients were treated VigiBase, hyponatraemia has been reported as an with other drugs (e.g. thiazides, loop diuretics, ADR in 0.4% of all reports in which neither carbamazepine, cisplatin, valproic acid, citalopram nor ramipril was taken. When looking mirtazapine, aripiprazole and omeprazole) that at the proportion of reports where hyponatraemia have hyponatraemia listed as an ADR in the SPC. is reported for the two drugs separately, one can see that hyponatraemia has been reported in The outcome was stated in 41 cases; the patient 4.4% when using citalopram alone compared to had recovered in 27 cases, was recovering in five 1.3% when using ramipril only. The corresponding cases and had not recovered in nine cases. Where percentage of reports where hyponatraemia was the patients had recovered or were recovering, described when taking both these drugs together there was a positive dechallenge for both was 32%, suggesting that combination treatment citalopram and ramipril in three cases. In 13 might increase the risk of developing this ADR. cases, citalopram alone was withdrawn prior to recovery. One positive dechallenge was also seen The 49 cases originate from nine countries; for ramipril, together with a dose reduction of Germany (15 cases), United Kingdom (12 cases), citalopram. Canada and France (six cases each), United States (four cases), Italy and Australia (two cases each), Two cases had fatal outcome, however, not Ireland and Sweden (one case each). The cases reported as related to hyponatraemia. In one case concern 38 females and 10 males (sex was not worsening of hyponatraemia was described in a specified in one report). Age was reported for 47 76-year-old male with multiple diseases including patients and ranged between 50 and 92 years with recurrent electrolyte imbalance, non-small cell a median of 78 years. lung cancer, depression, drug abuse, cerebral ischemia, chronic obstructive pulmonary disease A more comprehensive narrative was available in (COPD), arterial hypertension, and multiple drug 11 cases and detailed clinical information treatment. The drugs citalopram, bromazepam, regarding the patient and the event was thus gemicitabine and cisplatin were all suspected to lacking in many cases. have caused worsening of hyponatraemia. The Most ICSRs had no complete dates for treatment, patient did not recover from this event and the and information on time to onset was often lacking patient died due to an unknown cause of death. In for both of the drugs. In 20 cases, the reaction another case an 83-year- old female with heart occurred within the first six weeks of treatment failure, COPD and psychotic depression who with one of the agents. In two cases both drugs developed hyponatraemia during treatment with were started at the same day and time to onset ramipril and citalopram is described. Besides this were 24 days and three years, respectively. In 12 treatment she was treated with fluticasone, cases treatment with ramipril was started before formoterol, enoxaparin, digoxin, acetylsalicylic citalopram (from 10 days to several years) and acid, nebivolol and temazepam. She recovered but

WHO Pharmaceuticals Newsletter No. 2, 2014  11

SIGNAL according to the report, she died from an It is known that individuals taking multiple drugs unspecified cause two weeks after hyponatraemia recognized to cause hyponatraemia are at was normalized. increased risk. More than half of the patients were co-treated with diuretics or other medication that Literature and Labelling could possibly have caused or added to the hyponatraemia. A majority of the patients were Hyponatraemia is a labelled ADR in the SPC of female and/or elderly, which are both risk factors citalopram,8 but not a labelled ADR in the SPC of for hyponatraemia. Whether the risk for ramipril.9 The ADR is however described in the hyponatraemia during concomitant treatment of literature for ramipril10 and other ACE inhibitors.5 citalopram and ramipril is additively or Although it has been previously acknowledged that synergistically increased compared with the risk individuals taking multiple drugs known to cause when these drugs are used separately is not hyponatraemia are at increased risk,3,6,7 this drug possible to evaluate using the data from these interaction is not described in drug interaction ICSRs. sources such as Stockley’s Drug Interactions11 or Swedish Finnish Interaction X-referencing Conclusion (SFINX),12 possibly since many additive drug The proportion of ICSRs where hyponatraemia was interactions are not described in such drug reported for citalopram and ramipril taken interaction sources. A literature search in PubMed together in relation to when the drugs were taken did not reveal any published case reports where separately, together with the cases where the hyponatraemia was associated with the combina- reporter suspected both of the drugs of causing tion therapy of citalopram and ramipril. hyponatraemia, suggest that concomitant use of citalopram and ramipril is associated with an Discussion increased risk of hyponatraemia. This possible Hyponatraemia is a well-documented ADR to drug interaction is consistent with previously SSRIs including citalopram.1-4 In addition, ACE known pharmacological properties of these drugs inhibitors such as ramipril may induce and is supported by a plausible time course in hyponatraemia.5,8 several cases. It is previously known that individuals taking multiple drugs recognized to Comparing the proportion of ICSRs in VigiBase cause hyponatraemia is at increased risk. Whether where hyponatraemia is reported as an ADR when this risk is additively or synergistically increased taking citalopram or ramipril together (32%) to compared with the risk when using the drugs the proportion of reports where the ADR is separately is not possible to evaluate using these reported when taking both of the drugs separately data. It seems likely that this potential interaction (4.4% and 1.3%, respectively), demonstrates that may occur between other ACE inhibitors and SSRIs concomitant treatment with the two drugs might and the association should be evaluated further. increase the risk of developing hyponatraemia. There were 18 cases where the reporter suspected that both citalopram and ramipril played a part in References the development of hyponatraemia, and in three 1. Liamis G, Milionis H, Elisaf M. A review of drug- of these cases the reporter assessed both of the induced hyponatraemia. Am J Kidney Dis. 2008; drugs as interacting. 52(1):144-53. The analysis of the post-marketing cases revealed 2. Lien YH, Shapiro JI. Hyponatraemia: Clinical a rapid time to onset of hyponatraemia described diagnosis and management. Am J Med. in several cases. Twelve patients were already on 2007;120(8):653-8. ramipril treatment when citalopram was started, 3. Palmer BF, Gates JR, Lader M. Causes and and six of these patients developed hyponatraemia management of hyponatraemia. Ann within one to three days after starting citalopram. Pharmacother. 2003;37:1694-702. The quick onset of hyponatraemia in these six cases indicates that the sodium levels might also 4. Ellison DH, Berl T. Clinical practice. The have been influenced by ramipril. syndrome of inappropriate antidiuresis. N Engl J Med. 2007; 356(20): 2064-72. The information above is suggestive that concomitant treatment of citalopram and ramipril 5. Izzedine H, Fardet L, Launay-Vacher V, Dorent is associated with hyponatraemia. The suggested R, Petitclerc T, Deray G. Angiotensin-converting interaction is consistent with already known enzyme inhibitor-induced syndrome of pharmacological properties of these drugs. The inappropriate secretion of antidiuretic hormone: lack of relevant clinical information in most case report and review of the literature. Clin reviewed cases complicates the assessment. Pharmacol Ther. 2002;71:503-7.

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6. Movig KLL, Leufkens HGM, Lenderink AW, van 9. Summary of Product Characteristics for ramipril den Akker VGA, Hodiamont PPG, Goldschmidt HMJ (Ramipril). et al. Association between antidepressant drug use URL: http://www.medicines.org.uk/emc/ and hypo- natraemia: a case-control study. Br J medicine/24132/SPC/Ramipril+1.25mg+Capsules/ Clin Pharmacol. 2002;53(4):363-9. Accessed: 30 August 2013. 7. Jacob S, Spinler SA. Hyponatremia associated 10. Ramasamy I. Severe hyponatraemia during with selective serotonin-reuptake inhibitors in therapy with ramipril. BMJ Case Rep. 2009; older adults. Ann Pharmacother. bcr06.2009. 1932. 2006;40(9):1618-22. 11. Stockley IH, Baxter K, ed. Stockley’s drug 8. Summary of Product Characteristics for interactions Pharmaceutical Press; 2008. citalopram (Cipramil). 12. Böttiger Y, Laine K, Andersson ML, Korhonen URL: http://www.medicines.org.uk/emc/ T, Molin B, Ovesjö ML et al. SFINX-a drug-drug medicine/1070/SPC/Cipramil+Tablets/. interaction database designed for clinical decision Accessed: 30 August 2013. support systems. Eur J Clin Pharmacol. 2009;65(6):627-33.

Combined Ibuprofen and Metamizole treatment - Acute renal failure Prof. Staffan Hägg, Sweden or COX-2 specific NSAID3-6 and is a well- Summary documented adverse reaction to ibuprofen.1 The Acute renal failure is an established adverse drug biological mechanism for acute renal failure during reaction to ibuprofen and has been associated with NSAID treatment is inhibition of COX enzymes metamizole treatment in some published case with consequent decreased synthesis of reports. As of 5 May 2013 there were 24 reports of , which can lead to reversible renal acute renal failure in association with the ischemia, a reduction in glomerular filtration, and combination ibuprofen and metamizole in the WHO acute renal insufficiency.3,4 Global Individual Case Safety Report (ICSR) Database, VigiBase®. The suspected interaction The association between acute renal failure and between metamizole and ibuprofen to cause acute metamizole is less well documented. A number of renal failure is supported by a plausible time sporadic cases published in the literature and the pharmacological properties with COX inhibition course in several cases and is consistent with 7,8 previously known pharmacological properties of support an association. the drugs. Whether the risk is additively or synergistically increased compared with the risk Reports in VigiBase when using the drugs separately is not known As of 5 May 2013, twenty-four Individual Case from the literature and is difficult to evaluate using Safety Reports (ICSRs) of acute renal failure have these individual case safety report data. Taking been entered into the WHO Global ICSR Database, together the information reported in the ICSRs VigiBase® since 1982 where metamizole and indicates a relevant drug interaction that should be ibuprofen together have been reported as monitored. interacting, suspected and/or concomitant (Table 1). In 14 of the ICSRs, the drugs were reported as Introduction suspected or interacting which should be Ibuprofen is a non-steroidal anti-inflammatory compared to an expected 4.2. The omega value drug (NSAID), a class of medications widely used for these suspected interacting reports is 1.64 with for their analgesic and anti-inflammatory benefits. a lower credibility interval limit of 0.78, which Metamizole is a pirazolone derivative of analgesic shows a statistically significant association and antipyretic action, but without an anti- between acute renal failure and the combination inflammatory effect. Both ibuprofen and treatment of metamizole and ibuprofen in the metamizole inhibit cyclooxygenase (COX), but database. metamizole has a different mode of action compared to classical COX-inhibitors.1 NSAIDs are known to induce several different types of renal 2 injury including acute renal failure. This adverse reaction may occur with any non-selective NSAID

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Table 1. Case overview of ICSRs in VigiBase® of acute renal failure in association with ibuprofen and metamizole Case Age/ Other suspected or concomitant drugs Reactions (WHO-ART) Outcome of renal gender failure acute

1 33/F Cefalexin (S), lincomycin (C) Oliguria, renal failure acute, rash Recovered

2 24/F Spiramycin (C) Renal failure acute Recovered

3 70/M Indapamide (C), tiapride (C), tramadol (C) Nephritis interstitial, renal failure acute Recovered

4 75/M Rabeprazole (C), amitriptyline (C), terbinafine (S), allopurinol Rash maculo-papular, renal failure acute Recovered (S), pamidronic acid (I), chlortalidone (I), enalapril (I), (I)

5 39/F (S), diclofenac (S), piperacillin sodium/ tazobactam- Renal failure acute, cardio-respiratory failure, hepatitis cho- lestatic, Died sodium (C), amoxicillin sodium/clavulanate- potassium (C), hepato-cellular damage paracetamol (C), citalopram (C), isotretinoin (S)

6 86/M - Albuminuria, nephritis interstitial, renal failure acute Not recovered

7 56/F Tramadol (C), atenolol (C), isosorbide dinitrate (C), Neoplasm NOS, dysphonia, rash vesicular, oedema periphe- ral, Recovered enoxaparin(C), pantoprazole (C), (S) circulatory failure, jaundice, hepatic failure, renal failure acute

8 62M Homeopatics nos (C), calcium carbonate/quercus Renal failure acute Recovered petr-aea/quercus robur (C), Homeopathic preparation (C), bryophyllum pinnatum (C), homeopatics nos (C), dimetindene (C), amitriptyline (C), tramadol (C), simvastatin (C), furosemide (C), acetylsalicylic acid (C), pantoprazole (C), pregabalin (S)

9 35/M Azithromycin (C), NA (C), paracetamol (C) Renal failure acute Unknown

10 56/M Omeprazole (C), ibuprofen (I), fentanyl (I), valproic acid Renal failure acute, hepatitis, myocarditis Recovered (I), cetuximab (I)

11 16/M - Renal failure acute Recovered

12 32/M Acetylsalicylic acid (I), diclofenac (I), (I) Intentional overdose, renal failure acute Recovered

13 41/M - Thrombocytopenia, NA, purpura thrombopenic thrombotic, Recovering disseminated intravascular coagulation, thrombocytopenia, paraesthesia, LDH increased, dysphonia, haemolysis, hearing decreased, anaemia, renal failure acute

14 29/F (S), ciprofloxacin (S) Renal failure acute, anaemia normocytic, pharyngitis, Recovered sinusitis, fever, agranulocytosis

15 77/F Zoledronic acid (S), antineoplastic agents (C), esome- prazole Renal failure acute, azotaemia, sepsis, marrow depression, condition Died- reaction may be (C), bromazepam (C) aggravated contributory

16 45/F Lithium (I), naproxen (I), quetiapine (I), hyoscine (C) Speech disorder, ataxia, renal failure acute, drug level Not recovered increased

17 80/M Quinapril (S) Renal failure acute Recovered

18 24/F Paroxetine (C), amoxicillin (C), diclofenac (C) Renal failure acute Recovered

19 40/M Ciclosporin (I) Renal failure acute Recovered

20 39/M Tramadol (C), metamizole (S), amoxicillin sodium/ clavulanate Rash erythematous, rash maculo-papular, renal failure acute, Recovering potassium (S), paracetamol (C), diclofenac (S), cetirizine (C), nephrosis, nephritis interstitial ibuprofen (S)

21 50/F Hydrochlorothiazide/metoprolol succinate (C), NA (C), Azotaemia, creatinine clearance decreased, renal failure acute Recovered metformin (C), metoclopramide (S), loperamide (S), ramipril (S)

22 71/M NA (C), NA (C), acetylsalicylic acid (C), ramipril (C), NA (C), NA, creatinine clearance decreased, renal failure acute Recovered clindamycin (S)

23 51/M Astemizole (S), (S), ciprofloxacin (S) Renal failure acute Recovered

24 87/F Metformin (I), norfloxacin (I) Renal failure acute Recovering Abbreviations: M= male, F= female, S= suspected, I= interacting, C = concomitant, NA = not available

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Studying the number of reports submitted in damage, cholestatic hepatitis and cardio- VigiBase, acute renal failure has been identified to respiratory failure besides acute renal failure was be reported as an adverse drug reaction (ADR) in reported in a 39-year-old female treated with 0.6% of all reports in which neither ibuprofen nor different drugs, among these isotretinoin, which metamizole was taken. When looking at the was considered the suspected agent for the liver proportion of reports where acute renal failure is reactions. In the other case acute renal failure, reported for the two drugs separately, one can see sepsis, marrow depression, azotaemia, and that acute renal failure has been reported in 2.0% condition aggravated was reported acute in a 77- when using ibuprofen alone compared to 0.9% year-old female. Zoledronic acid and ibuprofen when using metamizole only. The corresponding were reported as suspected agents in this case. percentage of reports where acute renal failure was described when taking both these drugs Literature and Labelling together, was 7.7% suggesting that combination The interaction has not been described in available treatment might increase the risk of developing drug interaction sources such as Stockley’s Drug this ADR. Interactions9 or Swedish Finnish Interaction X- The ICSRs originate from four countries; Spain (13 referencing (SFINX).10 A literature search in cases), Germany (six cases), Switzerland (four Medline has not revealed any published cases cases) and Japan (one case) and concerned 14 where acute renal failure was associated with the males and 10 females. Their age ranged between combination ibuprofen and metamizole. 16 and 87 years with a median of 48 years. The time to onset for the reaction generally Discussion occurred within the first month of treatment in the Acute renal failure is a well-documented adverse majority of the reports. In eight of the ICSRs, both reaction to NSAIDs such as ibuprofen. In addition, of the drugs were reported as interacting. In three metamizole has been associated with acute renal cases only one of the two drugs was reported as failure although the available evidence is limited. interacting while the other drug was reported as Comparing the proportion of reports in VigiBase suspected or concomitant. where acute renal failure is reported as an ADR when taking both the drugs together (7.7%) Acute renal failure occurred within the first week compare to the proportion of reports where the of treatment with one of the agents in 13 cases. In ADR is reported taking ibuprofen or metamizole four cases (8, 10, 14 and 23) we could identify a separately (2.0% and 0.9% respectively), time-to- onset pattern. In case 8 and 10, the demonstrates that concomitant treatment with the patient had tolerated ibuprofen separately and two drugs might increase the risk for developing after adding metamizole to the treatment, acute acute renal failure. renal failure developed within two days of combined treatment. Case 14 and 23 showed an The review of the post-marketing cases, especially opposite reaction, the patient tolerated the 14 where the drugs were reported as metamizole separately and after adding ibuprofen suspected or interacting together with the eight to the treatment, acute renal failure developed. ICSRs where both ibuprofen and metamizole were reported as interacting, reveals that the reporter In three of the cases, the ADR occurred the same suspected a possible interaction between the day or within a day which indicates that other drugs which should be considered in the contributing factors such as dehydration might assessment. Studying all the ICSRs, a time-to- have influenced the development of acute renal onset pattern for developing the ADR was failure. Diclofenac, another NSAID drug, was taken identified in four cases after having added either together with ibuprofen and/ or metamizole in four ibuprofen or metamizole to the treatment. Taking cases, in one case as a long-term treatment with a this reported information together gives as an dose of 75 mg three times a week. This triple association that concomitant treatment with treatment might have added even more to the ibuprofen and metamizole could be associated with negative effects on the kidney. In one case the acute renal failure. patient had diabetes and was treated with metformin. This might have contributed to the In four cases, diclofenac was used as concomitant suspected ADR since diabetes increases the risk of drug which can be an additional risk factor for developing different types of kidney problems. acute renal failure. In three of the recovered cases the drugs were withdrawn at the same time, which The outcome was stated in 24 cases and it was makes it difficult to determine which one of the reported that the patient had recovered in 16 drugs that might have caused the ADR, but at the cases, was recovering in three cases, had not same time it demonstrates that these drugs recovered in three cases and that the reaction was together might increase the risk of developing fatal in two cases. In one fatal case hepatocellular WHO Pharmaceuticals Newsletter No. 2, 2014  15

SIGNAL acute renal failure. Although multi-ingredients conventional nonsteroidal antiinflammatory drugs drugs with both substances have been launched in with acute renal failure: A population-based, some countries, the combination treatment seems nested case-control analysis. Am J Epidemiol irrational from a pharmacological perspective and 2006; 164(9):881-9. should therefore probably be avoided. 3. Oates JA, FitzGerald GA, Branch RA, Jackson Whether the risk of acute renal failure during EK, Knapp HR, Roberts LJ 2nd. Clinical implications concomi- tant treatment of ibuprofen and of and thromboxane A2 formation metamizole is additi- vely or synergistically (1). N Engl J Med 1988; 319(11):689-98. increased compared with the risk when these 4. Patrono C, Dunn MJ. The clinical significance of drugs are used separately is difficult to evaluate inhibi- tion of renal prostaglandin synthesis. using spontaneously submitted reports. Kidney Int 1987; 32(1):1-12. Conclusion 5. Perazella MA. COX-2 selective inhibitors: The proportion of reports where acute renal failure analysis of the renal effects. Expert Opin Drug Saf is included as the reported ADR when taking the 2002; 1(1):53-64. two drugs together in relation to taking the drugs 6. Perazella MA, Tray K. Selective cyclooxygenase- separately, together with the ICSRs were the 2 inhibitors: a pattern of nephrotoxicity similar to reporter suspected an interaction between the traditional nonsteroidal anti-inflammatory drugs. drugs suggest that concomitant use of ibuprofen Am J Med 2001; 111(1):64-7. and metamizole is associated with acute renal failure. The possible interaction is also sup- ported 7. Böttiger Y, Laine K, Andersson ML, Korhonen T, by the four cases where a time-to-onset pattern Molin B, Ovesjö ML et al. SFINX - a drug-drug could be identified when adding either ibuprofen or interaction database designed for clinical decision metamizole together with the plausible time support systems. Eur J Clin Pharmacol. 2009 course in several cases which is consistent with Jun;65(6):627-33. previously known pharmacological properties of 8. Hassan K, Khazim K, Hassan F, Hassan S. Acute these drugs. Taking this together, the association kidney injury associated with metamizole sodium is regarded as a valid drug interaction and should ingestion. Ren Fail. 2011;33(5):544-7. be monitored. 9. Stockley IH, Baxter K, ed. Stockley’s drug References interactions Pharmaceutical Press; 2008. 1. Pierre SC, Schmidt R, Brenneis C, Michaelis M, 10. Böttiger Y, Laine K, Andersson ML, Korhonen Geisslinger G, Scholich K. Inhibition of T, Molin B, Ovesjö ML et al. SFINX-a drug-drug Cyclooxygenases by Dipyrone. Br J Pharmacol interaction database designed for clinical decision 2007; 151(4): 494-503. support systems. Eur J Clin Pharmacol. 2009;65(6):627-33. 2. Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and

Tocilizumab – Psoriasis and Aggravated psoriasis Signal strengthening Dr. Ruth Savage, New Zealand primarily affecting the skin. When the published Summary case reports together with VigiBase ICSRs for Tocilizumab inhibits the activity of the tocilizumab were combined, there was evidence of inflammatory cytokine interleukin (IL)-6. Its improvement with tocilizumab discontinuation or indications include rheumatoid arthritis and recurrence with each administration in four juvenile idiopathic arthritis. In the second quarter reports. Report characteristics indicate that there of 2013, after exclusion of three duplicates, the are similarities between reports of psoriasis WHO Global Individual Case Safety Report (ICSR) occurring with tocilizumab and those occurring Database, VigiBase® held 20 ICSRs of new onset with TNF inhibitors which have been well- or aggravated psoriasis attributed to tocilizumab. documented in the literature. The VigiBase ICSRs Four published case reports were also identified. provide additional evidence to the published case This suspected reaction is paradoxical since histories for tocilizumab. psoriasis is an autoimmune inflammatory disease

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Introduction The gender distribution was 15 females and four Psoriasis is an autoimmune inflammatory disease males in the combined ICSRs for the psoriasis and that usually presents with the development of aggravated psoriasis combinations. In one case inflammatory plaques on the skin. Studies have gender was not specified. Since the most frequent shown that it is likely that interactions between indication for tocilizumab was RA this observation dendritic cells, T cells, keratinocytes, neutrophils of female preponderance is not unexpected. Age and the cytokines released from immune cells was documented in only three of the 12 ICSRs for contribute to the initiation and perpetuation of the psoriasis but was recorded for seven of the eight cutaneous inflammation characteristic of patients with aggravated psoriasis. The range for psoriasis.1 Psoriasis affects about 2% of the the combined psoriasis and aggravated psoriasis population. In about 80% of patients psoriasis reports was 33 to 60 years and, for aggravated occurs as chronic plaque lesions. Palmoplantar psoriasis, 39 to 58 years with a median of 51 variants include plaque psoriasis confined to the years. palms and soles, and pustular lesions on these As well as RA, other indications for tocilizumab surfaces (palmoplantar pustulosis). Rarely, an were psoriatic arthropathy (two cases) and unrelated generalised and life-threatening seronegative rheumatoid arthritis (one case) in the pustulosis may develop. Another variant is guttate aggravated psoriasis group and juvenile arthritis psoriasis which presents as a rash of drop-like (one case) in the psoriasis group. While none of lesions, often after a beta-haemolytic the patients in the psoriasis group had a reported streptococcal infection. About 5% of patients with history of psoriasis, psoriatic arthritis may present 2-4 psoriasis develop an inflammatory arthropathy. as arthritis before psoriasis develops so the patient 2 Tocilizumab is a humanised anti-human interleukin with juvenile arthritis may have been redisposed. (IL)-6 receptor antibody. It competes for The recommended dose and dose frequency of membrane- bound and soluble forms of human IL- tocilizumab is 8 mg/kg monthly for adults with RA 6 receptor, thereby inhibiting the binding of this and 8 mg/kg two weekly for children weighing native inflammatory cytokine to its receptor and more than 30 kg with systemic JIA. Exceeding a interfering with the cytokine’s effects. This dose of 800 mg is not recommended.8 cytokine has the ability to activate T cells, B cells, macrophages and osteoclasts. Increased synovial The reports indicate that, where recorded, the fluid IL-6 levels correlate with disease activity in doses tended to be higher for the aggravated rheumatoid arthritis (RA) and circulating levels are psoriasis group compared with the psoriasis group, elevated in children with systemic juvenile although only one patient in the former group idiopathic arthritis (JIA). Its approved indications received greater than the recommended dose (880 include JIA and RA.5 mg). However, two patients whose dose intervals were shorter than recommended (weekly) were in In their respective summaries of product the psoriasis group. characteristics (SPCs), psoriasis is recognised as a possible adverse effect of tumour necrosis factor The duration of tocilizumab use to onset of (TNF) inhibitors and abatacept, a costimulation psoriasis was 1 to 85 days, median 19 days, for blocking soluble fusion protein.6,7 Like tocilizumab, the psoriasis group (four patients) and 5 to 191 both are biologic disease-modifying anti-rheumatic days, median 84 days, for the aggravated agents. psoriasis group (six patients). One patient had experienced a similar reaction to Reports in VigiBase rituximab, a biologic B-cell depleting agent whose In the second quarter of 2013, after removal of indications include autoimmune disorders, with three duplicates, there were 12 ICSRs for psoriasis recurrence on rechallenge. TNF inhibitors had been (Table 1) and eight for aggravated psoriasis (Table ineffective in this patient and had not caused 2) associated with tocilizumab use. The reports psoriasis (Table 2, ICSR1). There was no record of were from nine countries, the United States, the previous exposure to bio- logic antirheumatic United Kingdom, Italy, Belgium, Canada, Spain, medicines in the other reports. Five patients were Australia, Switzerland and Sweden. The taking methotrexate and one sulphasalazine, both combination tocilizumab/psoriasis aggravated of which are disease-modifying anti-rheumatic became statistically prominent in the second drugs (DMARDs). However, psoriasis is not a quarter of 2011 (IC 2.21, IC025 1.04) and recognized reaction to non-biologic DMARDs and tocilizumab/psoriasis in the first quarter of 2013 one study found no evidence that non-biologic (IC 0.96, IC025 0.14) when the total number of DMARDs caused or aggravated psoriasis in a 9 reports in VigiBase® for tocilizumab was 3,796. cohort of 2,880 patients.

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There was no consistent use of other medicines, Discussion and Conclusion suggesting an alternative explanation for psoriasis The reports in VigiBase do not overlap with or an interaction with tocilizumab. However, some published reports (Table 3) and provide additional ICSRs were not well-documented and information information. Published articles 1 and 2 in Table 3 on concomitant medicines or previous exposures indicate recovery when tocilizumab was may have been omitted. discontinued, one with recurrence on rechallenge. The psoriasis was described as guttate in two ICSR 3 in Table 1 indicates recovery on ICSRs of aggravated psoriasis and pustular in discontinuation and ICSR 9 in the same table three ICSRs of psoriasis. One patient with notes recurrence with each tocilizumab psoriasis had a bullous psoriatic reaction affecting administration. These provide support for the plantar area which was described as causality. Timing of report submission to national “impressive” and occurred several times, always centres with respect to when tocilizumab was after a tocilizumab infusion, (Table 1, ICSR 9). discontinued is not clear in some cases so that, for Two ICSRs indicated serious reactions. One patient the two patients (Table 2) who had not recovered with guttate psoriasis required hospital admission when tocilizumab was discontinued, sufficient time and one patient’s pustular psoriasis was assessed may not have elapsed for the psoriasis to resolve as disabling or incapacitating. when the report was submitted. The third report in Table 3 together with ICSR numbers 5 and 8 in the Of the 12 ICSRs for psoriasis, one patient with psoriasis group indicate that the patients pustular psoriasis was recovering after tocilizumab recovered while tocilizumab was continued, one was dis- continued, (Table 1, ICSR 3), and one with topical corticosteroid treatment. patient, descri- bed above, developed episodes of psoriasis, described as bullous and plantar, which The morphology of psoriasis occurring in always occurred after a tocilizumab infusion, association with biologic anti-rheumatic agent use (Table 1, ICSR 9). Three other patients recovered is also of interest. The vast majority of published or were recovering but the date of stopping cases of biologic DMARD-associated psoriasis have tocilizumab in relation to recovery was unclear or occurred with the TNF inhibitors. Analyses of case not documented. reports in the US FDA adverse events reporting system (AERS) database and the British Society Of the eight ICSRs for aggravated psoriasis, one for Rheumatology Biologics Register (BSRBR) have patient developed a massive increase in guttate provided information about the characteristics of psoriasis and seronegative rheumatoid arthritis these reports.6,9 In the FDA series of reports of five days after one dose of tocilizumab, (Table 2, patients taking a TNF inhibitor for non-psoriatic ICSR 1). This is the patient who had reacted indications about 17% of patients developed similarly five months previously to rituximab with palmoplantar and 15% pustular psoriasis. recurrence on rechallenge. Three patients with Palmoplantar pustular psoriasis predominated in aggravated psoriasis had not recovered at the the BSRBR reports, and guttate psoriasis was also time of reporting and the outcome was unknown reported. When the VigiBase ICSRs are combined for the remaining four. with the published tocilizumab reports, 8 of the 24 ICSRs (33%) describe pustular, palmoplantar or Literature and Labelling guttate psoriasis. Assuming that the remainder of There are three published articles describing the patients developed generalised plaque psoriasis or aggravated psoriasis occurring in four psoriasis (as the nature of their psoriasis was not patients during tocilizumab use (Table 3).10-12 The described), the proportion of patients with other indications were psoriatic and non-psoriatic. One types of lesions with tocilizumab is greater than young man also experienced a flare of pre-existing the 20% expected for psoriasis in general, uveitis. The form of psoriasis was palmoplantar in although a larger case series would be needed to one patient and guttate in another, in keeping with confirm this. observations in the VigiBase ICSRs. Two patients The mechanism whereby TNF inhibitors and recovered on dechallenge and one relapsed on tocilizumab might induce or aggravate psoriasis is rechallenge. However, this patient and one other unknown. Clearly this is a paradoxical reaction as tolerated further administrations while using these medicines inhibit the actions of pro- topical psoriasis treatment. This suspected inflammatory cytokines. IL-6 appears to have a reaction does not appear in Martindale, Drugdex, role in maintaining inflammation in psoriasis which the European Medicines Agency (EMA) Summary includes promoting TNF and other cytokine of Product Characteristics (SPC), or in the US Food production from T helper 17 cells which are and Drug Administration (FDA) label. important mediators in autoimmune diseases and host defence against extracellular pathogens.10

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However, as there is evidence for abatacept and biologic-agents-in-the-rheumatic-diseases. limited evidence for rituximab and anakinra Accessed: 18 June 2013. causing psoriasis and these are biologic anti- 6. FDA. Information for Healthcare Professionals: rheumatic agents with various effects on the Tumor Necrosis Factor (TNF) Blockers. URL: immune system,13 a specific mechanism related to http://www.fda.gov/Drugs/DrugSafety/Postmarket TNF and IL-6 inhibition is less likely. Cytokine DrugSafetyInformationforPatientsandProviders/ imbalance has been proposed as a possible DrugSafetyInformationforHeathcareProfessionals/ mechanism.10 ucm174474.htm. Accessed: 18 June 2013. The number of published and VigiBase ICSRs of 7. Orencia. Bristol-Myers Squibb PharmaEEIG URL: psoriasis occurring in association with TNF http://www.ema.europa.eu/docs/en_GB/document inhibitors far outweighs those for tocilizumab and _ library/EPAR_- the other biologic anti-rheumatic agents. This may Product_Information/human/000701/ partly reflect usage and the novelty of the WC500048935.pdf. Accessed: 2 July 2013. discovery of this reaction with TNF inhibitors leading to a greater likelihood of reporting, but 8. RoActemra. Roche Registration Ltd. further study to ascertain if there is a real URL: http:// difference between the agents with respect to this www.ema.europa.eu/docs/en_GB/document_librar adverse reaction would be clinically useful. For y/ EPAR_-_Product_Information/human/000955/ tocilizumab the published and VigiBase WC500054890.pdf. Accessed: 2 July 2013. spontaneous reports do suggest a possible causal relationship with the emergence or aggravation of 9. Harrison MJ, Dixon WG, Watson KD, King Y, psoriasis. Groves R, Hyrich KL et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha References therapy: results from the British Society for 1. Blauvelt A, Ehst BD. Pathophysiology of Rheumatology Biologics Register. Ann Rheum Dis. psoriasis. UpToDate. URL: 2009;68:209-15. http://www.uptodate.com/contents/pathophysiolo gy-of-psoriasis. Accessed: September 2013. 10. Laurent S, Le Parc JM, Clérici T, Bréban M, Mahé E. Onset of psoriasis following treatment 2. Feldman SR. Epidemiology, clinical with tocilizumab. Br J Dermatol. 2010;136:1364- manifestations and diagnosis of psoriasis. URL: 5. http://www.uptodate.com/ contents/epidemiology-clinical-manifestations- 11. Wendling D, Letho-Gyselinck H, Guillot X, Prati and-diag- nosis-of-psoriasis. Accessed: September C. Psoriasis onset with tocilizumab treatment for 2013. rheuma- toid arthritis. J Rheumatol. 2012;39:657. 3. British Association of Dermatologists. Psoriasis- 12. Lekpa FK, Poulain C, Wendling D, Soubrier M, an Overview. De Bandt M, Berthelot JM et al. Is IL-6 an URL: http://www.bad.org.uk/site/864/ appropriate target to treat Default.aspx. Accessed: September 2013. spondyloarthritispatients refractory to anti-TNF therapy? A multicentre retrospective observational 4. DermNet NZ. URL: study. Arthritis Res Ther. 2012;14:R53. http://www.dermnetnz.org/scaly/psoriasis- general.html. Accessed: September 2013. 13. Borchers AT, Leibushor N, Cheema GS, Naguwa SM, Gershwin ME. Immune-mediated 5. Stone JH. Overview of biologic agents in the adverse effects of biologicals used in the rheumatic diseases. UptoDate. URL: treatment of rheumatic diseases. J Autoimmun. http://www.uptodate.com/contents/overview-of- 2011;37:273-88.

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Table 1. Case overview of ICSRs in VigiBase® of psoriasis in association with tocilizumab

ICSR Sex/Age Indication Dose/Dose Duration Concomitant Psoriasis Outcome interval to onset medicines description 1 M/- Rheumatoid -/- - - Generalised Not arthritis recovered 2 F/- Rheumatoid 400 mg/- - - Pustular Unknown arthritis psoriasis 3 F/- Rheumatoid 280 mg/week One day Methotrexate Pustular Recovering arthritis psoriasis three weeks after stopping tocilizumab 4 F/- - -/- - - Psoriasis Drug withdrawn, Outcome unknown 5 F/33 Juvenile 8 mg/kg/week 17 days Paracetamol Psoriasis Recovering arthritis 6 M/- Rheumatoid 8 mg/kg - Prednisone Psoriasis Recovering arthritis /month Diclofenac 7 F/- Rheumatoid 8 mg/kg/- - Prednisone Psoriasis Unknown. arthritis 8 F/- Rheumatoid 360 mg/month 85 days Pustular Recovered arthritis Three doses, Methotrexate psoriasis one each Rebamipide month over 85 days prior to onset.

9 -/- Rheumatoid -/- - - Bullous, Not recorded arthritis plantar, psoriatic reaction, “impressive” 10 F/60 Rheumatoid 650 mg/week - Sulphasalazine Psoriasis (also Unknown arthritis Hydroxyzine folliculitis, Metronidazole conjunctivitis, Folic acid cyst)

11 M/- - -/- - Methotrexate Psoriasis Unknown 12 F/57 Rheumatoid 400 mg/ - 21 days Telmisartan Scalp Unknown arthritis Ticlopidine L- psoriasis thyroxine Methylprednisolone

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Table 2. Case overview of ICSRs in VigiBase® of psoriasis aggravated in association with tocilizumab

ICSR Sex/Age Indication Dose/Dose Duration Concomitant Psoriasis Outcome interval to onset medicines description 1 F/58 Rheumatoid 880 mg/ 5 days Pantoprazole Massive increase of Recovered arthritis, month duloxetine, widespread guttate seronegative One dose hydrochorothiazide/ psoriasis lesions given valsartan, and seronegative L-thyroxine, rheumatoid arthritis, sweating 2 F/49 Psoriatic 8 mg/kg / 55 days Methotrexate Psoriasis Unknown arthritis month aggravated 3 F/41 - 760 mg/- 111 days Methotrexate Guttate psoriasis, Unknown sharp flare with seeding over body within one week of receiving tocilizumab 4 F/56 Rheumatoid 400 mg/- 191 days Methylprednisolone, Psoriasis Unknown arthritis telmisartan, aggravated ticlopidine, L-thyroxine, fenofibrate 5 F/- Rheumatoid -/- - - Psoriasis Unknown arthritis aggravated, Anaemia 6 M/51 Psoriatic -/- 6 days - Psoriasis Not recovered arthropathy aggravated 7 F/54 Rheumatoid 800 mg/- 143 days Codeine/paracetamol, Psoriasis Not recovered arthritis celecoxib, aggravated colecalciferol 8 F/39 Rheumatoid 800 mg/- - - Psoriasis Not recovered arthritis, other aggravated

Table 3. Published reports of psoriasis with tocilizumab use10-12 ICSR Sex/Age Indication History of Dose Duration Concomitan Psoriasis Outcome Psoriasis to onset t medicines description 1 F/37 Still’s disease Yes 8 mg/kg/ 10 days Prednisone Scaly Recovered on month erythematous dechallenge with lesions increased oral and On rechallenge application palmoplantar and of topical pubic areas corticosteroids. affected Relapsed on rechallenge 2 F/52 Psoriatic Yes 8 mg/kg/ 5 days - Guttate Recovered on arthritis month dechallenge within one month 3 F/55 Rheumatoid No 8 mg/kg/ 63 days Prednisone No description Recovered with arthritis month Sites – leg, topical treatment elbow and tocilizumab continuation

4 M/19 Ankylosing Yes 8 mg/kg/ Not stated Predisone, Psoriasis “flare” Not stated spondylitis, month for NSAID uveitis at least 3 unspec, months methotrexate

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Response from Roche The Uppsala Monitoring Centre (UMC) of the WHO back to tocilizumab treatment and manage her Collaborating Centre for International Drug psoriasis symptoms with topical steroids instead. Monitoring, identified psoriasis as a technical The last case of psoriasis had prior history of signal in their Global ICSR database Vigibase® cutaneous eruptions. The patient developed based on calculated Information Component (IC) exacerbation of the lesion after the 3rd tocilizumab values. 12 ICSRs for psoriasis and 8 ICSRs for dose. The status of psoriasis as well as the aggravated psoriasis were identified in the second tocilizumab treatment was not provided. These quarter of 2013, after removal of three duplicates. cases are included in the cumulative review “The combination tocilizumab/ psoriasis completed by Roche described above. aggravated became statistically prominent in the Of note, in the published literature, there are also second quarter of 2011(IC 2.21, IC025 1.04) and case reports describing the successful use of tocilizumab/psoriasis in the first quarter of 2013 tocilizumab in patients with psoriatic arthritis1 or (IC 0.96, IC025 0.14) when the total number of anti-TNF induced palmoplantar pustulosis, which is reports in Vigibase® for tocilizumab was 3,796.” a type of psoriasiform lesion2. Roche has been invited to comment on this In conclusion, there does not appear to be a technical signal relating to tocilizumab and causal relationship between psoriasis and psoriasis. The safety of patients is of the utmost tocilizumab. Roche will continue to monitor this importance to Roche, and adverse event reports condition. No updates to the product information from patients and physicians taking our medicinal documents and no changes to the conduct of products in clinical trials and in the post-marketing clinical trials are warranted at this point in time. setting are continuously monitored and assessed. Roche will continue to monitor and obtain as much These events are reported to regulatory information as possible on received reports. The authorities in accordance with the respective benefit/risk assessment of tocilizumab remains regulations and safety guidelines. unchanged. Roche uses the MedDRA coding dictionary for its Global Drug Safety Database ARISg, which References: includes spontaneous reports from the post- 1. Hughes M, Chinoy H. Successful use of marketing setting and serious adverse events and tocilizumab in a patient with psoriatic arthritis. non-serious adverse events of special interest Rheumatology (Oxford). 2013 Sep;52(9):1728-9. from clinical trials. In MedDRA, the High-Level Term (HLT): psoriatic conditions and the HLT: 2. Rueda-Gotor J, González-Gay MA, Blanco psoriatic arthropathies was used to identify Alonso R. potential cases of psoriasis and then a cumulative Successful effect of tocilizumab in anti-TNF-α- review (through 10 April 2013) of these potential induced palmoplantar pustulosis in rheumatoid psoriasis events was performed. arthritis. Joint Bone Spine. 2012 Oct;79(5):510-3. This cumulative review showed that a majority of reported cases contained minimal information precluding definitive causality assessment. About 20 % of reported cases had a preexisting history of psoriasis and an additional ~15% cases were reported with his- tory of anti-TNF use. As stated in the article above, the vast majority of published cases of biologic DMARD- associated psoriasis have occurred with the TNF inhibitors. The four cases of psoriasis cited in the literature, that describe evidence on positive re-challenge or positive de-challenge are described as follows: two of the 4 cases had history of anti-TNF use. One case discontinued tocilizumab treatment with resolution of psoriasis symptoms; however, the patient’s RA symptoms recurred. She opted to go

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Vemurafenib and Pancreatitis Daniele Sartori, Uppsala Monitoring Centre the treatment of metastatic melanoma, Summary vemurafenib was found to halt the progression of Vemurafenib is a serine threonine protein kinase stage III and stage IV previously untreated V600E inhibitor, which inhibits the kinase activity of mutation positive melanomas for a median of 5.4 mutated B-Raf protein. The drug received FDA months versus 1.6 months.4 Animal studies on approval in August 2011 for use in the treatment vemurafenib did not reveal pancreatitis.5 Reported of metastatic or unresectable malignant melanoma common adverse reactions during randomized that is positive for the BRAF V600E mutation. This clinical trials were: arthralgia, rash, fatigue, molecule interferes with the RAS-RAF-MEK-ERK photosensitivity, cutaneous squamous cell pathway, which is involved in the regulation of cell carcinoma, keratoacanthoma, nausea, alopecia, proliferation, survival, differentiation and pruritus, hyperkeratosis, diarrhoea, headache, and apoptosis. As of September 2013, 20 Individual vomiting.4,6 Case Safety Reports (ICSRs) have been submitted from seven different countries to the WHO Global Acute pancreatitis is a clinical condition, the ICSR Database, VigiBase®, in which vemurafenib annual incidence of which is 4.9 to 35 per 100,000 is associated with pancreatitis. Several reports people, characterized by inflammatory symptoms showed similarities in terms of dosage of individual degrees of manifestation; it can be administered, time to onset, laboratory values, self-limiting to the point of not requiring treatment outcome and in many cases vemurafenib was the but may also be severe (25% of the cases), only drug reported. In the following assessment leading to death due to multi-organ failure (30- 50% mortality associated with severe the evidence for a possible link between 7,8 vemurafenib and pancreatitis, a serious and pancreatitis; the majority of cases follow an acute course, but 3 to 13% of the cases become potentially life-threatening condition was 9 examined. In addition to the cases identified chronic). The pathophysiological mechanisms during the routine screening of VigiBase, we also leading to acute pancreatitis have yet to be fully examined reports for vemurafenib that included understood. It is accepted that the initial related terms for increased amylase and lipase inflammatory response involves the destruction of enzymes, which may also indicate pancreatitis. acinar cells through apoptotic or necrotic Evidence to support a signal between vemurafenib mechanisms with consequent leakage of and pancreatitis included: an analogy with other pancreatic digestive enzymes, effectively leading kinase and BRAF inhibitors suggesting a plausible to an autodigestion of the organ. A number of mechanism of action, coherence in laboratory factors may contribute to the development of findings (increased lipase and amylase values) pancreatitis, including but not limited to gallstones (38% of the cases), alcohol abuse (36%), that indicate pancreatic sufferance, consistency in 7,10 terms of posology and temporal response after infectious or toxic causes. Laboratory tests for drug intake. the diagnosis of pancreatitis involve amylase and lipase measurements. Drug induced pancreatitis inci- dence is estimated to be 0.1-2%.11 Time to Introduction onset for drug induced pancreatitis varies greatly Vemurafenib (Zelboraf®), a serine threonine as it could range from one day to several protein kinase inhibitor, received FDA approval in months.12,13 August 2011 for use in the treatment of metastatic or unresectable malignant melanoma that is positive for the BRAF V600E mutation. The drug is active in the RAS-RAF-MEK-ERK pathway, which is involved in the regulation of cell proliferation, survival, differentiation and apoptosis. Vemurafenib competes with adenosine- triphosphate (ATP) to reversibly and selectively inhibit the V600E mutated BRAF kinase, by preventing its phosphorylation mediated activation.1 The drug is administered orally as 240 mg tablets,2 usually 3-8 tablets per day.

Vemurafenib is metabolized by CYP3A4 and mostly excreted in the faeces (94%), up to 5% of its metabolites can be found in plasma.3 Compared to dacarbazine, the only other FDA approved drug for WHO Pharmaceuticals Newsletter No. 2, 2014  23

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Table 1. Vemurafenib and pancreatitis – Characteristics of 18 cases retrieved in VigiBase® Case Age/ Time to Duration of Other suspected (S) or Reactions (WHO-ART) Dechallenge/ Outcome Gender onset treatment concomitant (C) drugs Rechallenge (pancreatitis) 1 -/F 81 days 126 days Venlafaxine (C) Pleuritic pain, pleural Positive Recovered with effusion, squamous cell dechallenge/- sequelae carcinoma of skin (MedDRA), pancreatitis 2 -/M 15 days 18 days - Pancreatitis, abdominal pain Drug withdrawn/ Not recovered Rechallenge 3 -/F 4 days 4 days Lisinopril, diltiazem (both C) Lipase increased, Positive Recovered pancreatitis dechallenge/- 4 21/F 59 days 64 days - Pancreatitis Drug Died (disease withdrawn/- progression) 5 -/M - - - Arthralgia, fatigue, Unknown/- Unknown pancreatitis, myalgia, nausea 6 -/F - - Clonidine, omeprazole, potassium, Renal failure, arthralgia, Unknown/- Unknown valaciclovir, glipizide, docusate, pyrexia, diarrhoea, rash, valsartan/amlodipine besilate, pancreatitis metoprolol, hydrochlorothiazide, metformin (all C) 7 35/F 5 days 5 days - Pancreatitis Positive Recovered dechallenge/ Re-introduced at lower dose (outcome unknown) 8 35/M - 370 days - Pancreatitis, lipase increased Drug Unknown withdrawn/- 9 62/M 5 days - - Pancreatitis -/- Recovered 10 -/M - - - Pancreatitis, gastroenteritis -/- Unknown viral, Guillain-Barré syndrome, hepatitis

11 76/M 3 days 3 days Acetylsalicylic acid, iodine, Pancreatitis acute Positive Recovered levothyroxine (all C) dechallenge/- 12 -/M 1-60 days - - Pancreatitis, brain Dose lowered/- Unknown, metastases patient died of underlying disease 13 60/M - - - Hepatitis, hepatic function -/- Not recovered abnormal, Guillain-Barré syndrome, paraneoplastic syndrome (MedDRA), polyneuropathy chronic (MedDRA), paralysis facial, gastroenteritis viral, pancreatitis 14 59/M 4 days > 4 days - Pancreatitis, erysipelas Drug Recovering withdrawn/- 15 75/M 29 days 30 days Timolol, Metamizole, Fentanyl, Pancreatitis necrotizing, Drug Unknown Finasteride, Candesartan, Sodium cholecystitis, acute renal withdrawn/- bicarbonate/potassium chloride/ failure Sodium chloride/Macrogol 3350 (all C) 16 80/F 156 days 156 days , Sodium bicarbonate/ Pancreatitis Positive Recovered Potassium chloride/Sodium chloride/ dechallenge/- Macrogol 3350, Sodium picosulfate, acetylsalicylic acid, levothyroxine, pantoprazole, domperidone (all S) 17 67/M - - Codeine phosphate/paracetamol, Abdominal pain, pancreatitis Unknown/- Unknown acetyl l-caretene (all C) 18 70/F 41 days - More than 20 drugs, including More than 30 terms, Unknown/- Recovered, died lisinopril (C), Piperacillin sodium/ including pancreatitis from respiratory Tazobactam sodium (S) failure

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and so is the month of reaction onset. In the Reports in VigiBase remaining six cases, there are no specified dates A total of 20 Individual Case Safety Reports or only the starting day was reported. (ICSRs) of vemurafenib associated with pancreatitis were retrieved from the WHO Global Amylase values were included in four cases, one of ICSR Database, VigiBase® on 23 September which was confounded by metastases, and ranged 2013. This combination has been identified as roughly between 3 and 16 times the upper limit of statistically disproportionate with an IC of 1.42 normal. and an IC025 of 0.72. After the exclusion of two Lipase values were included in three reports and duplicates, 18 ICSRs were reviewed case by case ranged from 10 to 30 times the upper limit of (Table 1, page 52). The additional search terms normal. amylase increased and lipase increased yielded a further five cases, two of which had already been In case 3a (Table 2), the MAH reported an captured using the pancreatitis search term, “analysis of similar events” related to lipase bringing the total number of cases for the increased values. It was stated that three cases assessment. The lipase and amylase results have were found in the MAH database, one of which was been summarized in Table 2. All patients were assessed as related to vemurafenib while two were either affected by malignant melanoma or not (due to a prior history of pancreatitis). metastatic malignant melanoma. In five of 18 cases, a positive dechallenge could be The 18 ICSRs reporting pancreatitis came from the seen. In 10 of the 18 cases the drug was United States (nine), Australia (three), Germany withdrawn; five recovered or were recovering, one (two), Austria (one), Switzerland (one), Croatia recovered with sequelae, one did not recover (in (one) and Hungary (one). Sex was provided for all this case the medication was reintroduced but no cases, 11 of the patients were males. Age was not outcome information was provided), one died specified in eight of the cases; of the remaining 10 (cause of death was said to be disease for which age was provided, three of the patients progression) and in two patients the outcome of were between 18-44, three ranged from 45 to 64, the dechallenge was unknown. One of the five three were 65-75 and two were more than 75 patients that recovered was re-exposed at a lower years old. Dose regimens were specified in 12 dose and there was no recurrence of pancreatitis. cases, the most common being 1920 mg per day In one case the dose was lowered and the (eight cases). Vemurafenib was the only suspected outcome of pancreatitis was unknown. Of the drug in 16 cases and the only reported drug in 10 seven remaining patients no information was cases. Co-suspected drugs were reported in only provided on the action taken in relation to two ICSRs and those are listed, along with other vemurafenib: the outcome was reported as concomitants, in Table 1. In only three cases recovered for two patients, not recovered for one concomitants for which pancreatitis is listed in the patient and unknown for the remaining four. Summary of Product Characteristics were identified: case 3 and 18 (lisinopril) and case 6 Co-morbidities included: pancreatic metastases (valsartan/amlodipine besilate and (case 4), diabetes (case 6 – formally not reported, hydrochlorothiazide). However, in case 18, a list of but patient undergoing diabetes type II therapy, more than 20 drugs was reported but no dates of case 18), polyneuropathy, lung metastasis and treatment were provided. anaemia (case 11), brain metastasis (case 12), hypertension (case 6, 15, 18). The patient’s weight alone was reported in six cases: 64 kg (case 1), 90 kg (case 2), 166 kg Causality was assessed as “possible” by the (case 3), 99 kg (case 6), 66 kg (case 7), 72 kg reporters in five cases, two of which were reported (case 18). Sufficient information to calculate Body by the manufacturer, it was assesed as“certain” in Mass Index was provided in only one case, (case one case and “related” in another two. Where co- 11, BMI 28). History of alcohol abuse and suspected drugs were specified, causality was gallstones was not reported for any of the considered as “unlikely”. patients. Time to onset was clearly reported in 11 cases and ranged between three days to five months. In one occasion (case 12) the exact start date was not reported although the starting month is known

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Table 2. Vemurafenib and lipase and amylase increased – Characteristics of 3 cases retrieved in VigiBase®

Case Age/ Time Duration Other suspected (S) Lipase/Amylase Dechallenge/ Outcome to of or concomitant (C) values/Normal Rechallenge Gender onset treatment drugs and underlying reference values conditions 1a 44/M 6 days 6 days Lacosamide, tramadol, Lipase: 686 U/L/? Lowered dose/- Recovering mirtazapine, pantoprazole, metamizole, lorazepam, levetiracetam, dexamethasone, calcium (all C) 2a 46/F 7 days 7 days Hysterectomy nos, Lipase: 141 U/L/? Unknown/- Unknown hypertension arterial, smoker Amylase: 132 U/L/? 3a 63/F 26 26 days Dexamethasone, etoricoxib, Lipase: 524 IU/L/<60 Positive Recovering days metamizole, gentamicin, dechallenge/- bethamethasone valerate/ fusidic acid, pregabalin, zopiclone, lorazepam, ibuprofen, aciclovir, urea- cresol-sulfonate sodium, pantoprazole (all C)

have a very rare potential to induce pancreatitis, Literature and Labelling according to the UK SPC. Drug withdrawal led to Neither the European Medicines Agency (EMA) recovery in ICSRs 3, 7 and 11. Summary of Products Characteristis (SPC) nor US FDA labels indicate pancreatitis as a potential Secondly, the interruption of the RAS-RAF-MEK- adverse reaction; moreover, there was no mention ERK cascade by vemurafenib results in the activation of caspase-9; this enzyme has been of either increased amylase or increased lipase 17 enzymes. Gamma-glutamyltransferases, potential found to promote apoptosis. Caspase-induced indicators of pancreatic inflammation, but more apoptosis has been pro- posed as one of the pathophysiological mechanisms for acute commonly associated with hepatobiliary problems, 7 3,14 pancreatitis. Alternatively, low dose vemurafenib were found to be increased in phase III studies. 18 There is one case report in the literature of a 49- can result in paradoxical induction of ERK, which could activate TNF-α dependant transcription year-old male with stage IV melanoma who 17 developed pancreatitis two weeks after starting factors such as NF-κB that may be linked to acinar cell apo- ptosis and ultimately acute treatment with vemurafenib. He recovered 7,19 following withdrawal of the drug, but pancreatitis pancreatitis,. recurred on rechallenge. His symptoms In relation to a possible mechanism, it is useful to disappeared after permanent discontinuation of consider drugs that share similar vemurafenib. All other possible causes were ruled pharmacodynamic properties with vemurafenib. At 15 out. least two other kinase inhibitors are known to cause pancreatitis: dabrafenib and sorafenib. The Discussion and Conclusion frequency with which sorafenib can induce There are several factors that point towards a pancreatitis has been defined as “uncommon” in causal association between vemurafenib and both the UK SPC and US FDA leaflet, while pancreatitis. Firstly, the evidence of recurring dabrafenib, according to the US FDA label, induced patterns in the reports. Without considering the pancreatitis in less than 10% of the patients. reports that present underlying conditions such as Protein kinase inhibitors interfere with the diabetes,16 pancreatic metastases or downstream effects of growth factors, such as VEGF; this inhibition has been linked by some cholecystolithiasis, which can act as con- founders, 20 there are several cases that bear similarities in authors to acute pancreatitis of ischemic origin. time to onset: cases 3, 7, 9, 11, 14. The dose was Sorafenib, a multi kinase inhibitor, acts on a also consistent in these (1920 mg per day), except broader spectrum of kinases than vemurafenib, for case 14 where it was unknown. Although there- fore it is possible that an alternative patient 3 was undergoing anti-hypertensive mechanism may be involved in the development of therapy with lisinopril, this drug is considered to pancreatitis; however, dabrafenib acts more closely to vemurafenib21 hence it is plausible that WHO Pharmaceuticals Newsletter No. 2, 2014  26

SIGNAL these drugs share a common mechanism in the 7. Bhatia M, Wong FL, Cao Y, Lau HY, Huang J, development of pancreatitis. It should be borne in Puneet P et al. Pathophysiology of acute mind the pathophysiology of pancreatitis is not yet pancreatitis. Pancreatology. 2005; 5(2-3):132-44. well understood.7,10 Epub 2005 Apr 21. It is not possible to rule out obesity as a cause of 8. Vege SS, Yadav D, Chari ST. Pancreatitis. In: GI gallstone-induced pancreatitis, but most ICSRs Epidemiology, 1st ed, Talley NJ, Locke GR, Saito lack data on essential parameters for a simple YA (Eds), Blackwell Publishing, Malden, MA 2007. assessment, such as BMI calculation. 9. Sekimoto M, Takada T, Kawarada Y, Hirata K, The elevation of enzymes in cases 1a, 2a, 3a, Mayumi T, Yoshida M et al. JPN Guidelines for the followed a similar temporal development to the management of acute pancreatitis: epidemiology, pancreatitis cases, in terms of time to onset, thus etiology, natural history, and outcome predictors the role of vemurafenib cannot be excluded. in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2006;13(1):10-24. Evidence to support a signal include: (i) the temporal association between drug administration 10. Wang GJ, Gao CF, Wei D, Wang C, Ding SQ. and the onset of the reaction is consistent through Acute pancreatitis: Etiology and common several cases, (ii) similar drug mechanisms induce pathogenesis World J Gastroenterol. 2009; the same adverse reaction, (iii) five patients 15(12): 1427-30. recovered after drug withdrawal. It should also be 11. Balani AR, Grendell JH. Drug-induced noted that the malignancy does not commonly pancreatitis: incidence, management and metastasize to the pancreas22 and no evidence of prevention. Drug Saf. 2008; 31(10):823-37. pancreatic metastasis was reported in the majority of the cases. Hence, it is plausible to hypothesize a 12. Urbánek K, Vinklerová I, Krystyník O, causal relationship between vemurafenib and the Procházka V. Acute pancreatitis induced by drugs. onset of pancreatitis in genetically predisposed Acute Pancreatitis, 2012-01-18 N1 26183 UR. individuals, at a dosage of 1920 mg per day. January 18, 2012 13. Tatley M. Drug-Induced Pancreatitis: An References Unlucky DIP. URL: 1. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK www.medsafe.govt.nz/profs/PUarticles/pancreati- mit- ogen-activated protein kinase cascade for the tis.htm. Accessed: 25 September 2013. treatment of cancer. Oncogene. 2007 May 14;26(22):3291-310. 14. Canadian Product Monograph for Vemurafenib. URL: http://webprod5.hc-sc.gc.ca/dpd-bdpp/item- 2. Ravnan MC, Mazen S, Matalka, MBA. iteme. do?pm-mp=00017920. Vemurafenib in Patients With BRAF V600E Accessed: 25 September 2013. Mutation-Positive Advanced Melanoma. Clin Ther. 2012 Jul;34(7):1474-86. 15. Muluneh B, Buie LW, Collichio F. Vemurafenib- associated pancreatitis: case report. 3. US Food and Drug Administration. Zelboraf Pharmacotherapy. 2013 Apr; 33(4):e43-4. Label (September 2013) URL: http://www.accessdata.fda.gov/ 16. Garg R, Chen W, Pendergrass M. Acute drugsatfda_docs/label/2013/202429s002s003lbl.p pancreatitis in type 2 diabetes treated with df. Accessed: 21 September 2013. exenatide or sitagliptin. Diabetes Care. 2010 Nov; 33(11):2349-54. 4. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al. Improved Survival 17. McCubrey JA, Steelman L, Chappell WH, with Vemurafenib in Melanoma with BRAF V600E Abrams SL, Wong EWT, Chang F et al. Roles of the Mutation. N Engl J Med. 2011 Jun 30; Raf/MEK/ ERK pathway in cell growth, malignant 364(26):2507-16. transforma- tion and drug resistance. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. 5. Summary of Products Characteristics for Zelboraf (Ustekinumab 240 mg film-coated 18. Poulikakos IP, Zhang C, Bollag G, Shokat KM, tablets). URL: http:// Rosen N. RAF inhibitors transactivate RAF dimmers www.medicines.org.uk/emc/medicine/26056. and ERK signaling in cells with wild-type BRAF. Accessed: 21 September 2013. Nature. 2010 March 18; 464(7287):427-30. 6. Flaherty KT, Robert C, Hersey P, Nathan P, 19. Rakonczay Jr Z, Hegyi P, Takàcs T, McCarrol J, Garbe C, Milhem M et al. Improved Survival with Saluja AK. The role of NF-κB activation in the MEK Inhibition in BRAF-Mutated Melanoma. N Engl pathogenesis of acute pancreatitis. Gut J Med. 2012 Jul 12; 367(2):107-14. 2008;57:259-67.

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20. Pezzilli R, Corinaldesi R, Morselli-Labate AM. melanoma. Drug Des Devel Ther. 2012;6:391- Tyrosine kinase inhibitors and acute pancreatitis. 405. JOP. J Pancrease (Online) 2010 May 5;11(3):291- 22. Zbytek B, Carlson JA, Granese J, Ross J, Mihm 3. MC Jr, Slominski A. Current concepts of metastasis 21. Menzies AM, Long GV, Murali R. Dabrafenib in mela- noma. Expert Rev Dermatol. 2008 and its potential for the treatment of metastatic October; 3(5):569-85.

Response from Roche Thank you for providing Roche an opportunity to reported as abnormal pancreatic enzymes. Each read and comment on the signal of Pancreatitis. case was then medically reviewed to assess causal relation- ship. Causality assessment was mainly As early as July 2012, an assessment was based on onset latency, absence of major conducted by Roche following identification by confounding factors and positive rechallenge (if both Roche and the EMA Pharmacovigilance Risk documented). Of the 31 cases, 13 cases were Assessment Committee of pancreatitis as a assessed as probable pancreatitis based on a potential signal. At that time, eighteen (18) predefined case definition, of which only 5 were reports of pancreatitis had been received when the assessed to have a likely causal association to estimated exposure worldwide to vemurafenib was vemurafenib. This review was submitted with the 4,500 corresponding to a reporting rate of 0.40%. Periodic Safety Update Report covering the period Of the 18 reports, 12 cases were from clini- cal 17 August 2013 to 16 February 2013. studies. Overall, these 12 cases did not suggest a particular pattern of time to onset or duration. Roche also followed up with the authors of the Four cases were reported in the first week (day 1, Literature article that the WHO has referenced in 2, 3, and 6) and the rest were distributed across a their article: Vemurafenib associated pancreatitis: wide range of time points up to 2 years after start case report. Muluneh, B., Buie, L W and Collichio, of vemurafenib treatment. Similarly, the duration F. Feb 22, 2013, Pharmacotherapy. In our of the AE ranged from 3 to 158 days. The conference call with one of the authors, it was remaining 6 cases were from spontaneous reports confirmed that although the patient was with very limited data available. Case analysis also hospitalized for this event, the diagnosis of acute revealed one or more confounding factors in the pancreatitis was not supported by CT or 18 cases such as concomitant medications, history ultrasound and that the positive rechallenge of pre-existing pancreatitis, hyperlipidemia, diagnosis was not confirmed by either imaging or gallstones, and metastases to the pancreas. The pancreatic enzymes and was based on an episode review concluded that there was no definitive of “epigastric pain”. evidence to show a causal association between In addition, the number of reported cases of pan- vemurafenib and pancreatitis based on the safety creatitis was compared to the background information of the 18 case reports. In addition the incidence of pancreatitis among patients with incidence of pancreatitis seen was within the rate distantly metas- tatic melanoma from 3 observed among malignant melanoma patients databases. Using a conservative analysis, whereby from other databases (Surveillance Epidemiology all the 24 reports of pancreatitis (as of 04 March and End Results (SEER), US Healthcare Claims). 2013) are considered, and with an estimated This review was presented within the Periodic exposure worldwide to Zelboraf at 14,283 patients Safety Update Report covering the period 17 (as of February 2013), this corresponds to a February 2012 to 16 August 2012. reporting rate of 0.16%. This is in the same range A second assessment on this signal was again as the incidence seen in the General Practice undertaken in February to March of this year. Research Database, MarketScan and SEER (GPRD Cumulative review of information from pre-clinical, database: 0.18%, MarketScan: 0.6% and SEER published literature, and the Roche safety data (men and women combined): 1.3% (95% CI: database (cut-off date of 04 March 2013) was 0.4 – 2.3). performed. In this assessment, the Roche global The second review also concluded that there was safety database was searched using the Standard no strong evidence to suggest a causal association MedDRA Query (SMQ) for acute pancreatitis. between vemurafenib and acute pancreatitis. Overall, 31 cases were retrieved of which 24 cases Roche continues to closely monitor the event of were reported as pancreatitis and 7 cases were pancreatitis.

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WHO Collaborating Centre Tel: +46-18-65 60 60 Fax: for International Drug Monitoring +46-18-65 60 88 E-mail: Box 1051, SE-751 40 Uppsala, Sweden [email protected]

CAVEAT DOCUMENT

Accompanying statement to data released from the Uppsala Monitoring Centre, WHO Collaborating Centre for International Drug Monitoring

Uppsala Monitoring Centre (UMC) in its role as the WHO Some National Centres that contribute information to VigiBase Collaborating Centre for International Drug Monitoring make an assessment of the likelihood that a medicinal product receives reports of suspected adverse reactions to medicinal caused the suspected reaction, while others do not. products from National Centres in countries participating in the WHO pharmacovigilance network, the WHO Programme for Time from receipt of a report by a National Centre until submission to UMC varies from country to country. International Drug Monitoring. Limited details about each Information obtained from UMC may therefore differ from suspected adverse reaction are received by the UMC. The those obtained directly from National Centres. information is stored in the WHO Global Individual Case Safety Report database, VigiBase. It is important to understand the For the above reasons interpretations of adverse reaction limitations and qualifications that apply to this information and data, and particularly those based on comparisons its use. between medicinal products, may be misleading. The supplied data come from a variety of sources. The The reports submitted to UMC generally describe no more than likelihood of a causal relationship is not the same in all suspicions which have arisen from observation of an reports. Any use of this information must take these unexpected or unwanted event. In most instances it cannot be factors into account. proven that a specific medicinal product (rather than, for example, underlying illness or other concomitant medication) is Some National Centres strongly recommend that anyone who the cause of an event. intends to use their information should contact them for interpretation. Reports submitted to National Centres come from both Any publication, in whole or in part, of information obtained regulated and voluntary sources. Some National Centres accept from UMC must include a statement: reports only from medical practitioners; other National Centres accept reports from a broader range of reporters, including (i) regarding the source of the information, patients. Some National Centres include reports from (ii) that the information comes from a variety of sources, pharmaceutical companies in the information submitted to and the likelihood that the suspected adverse reaction is UMC; other National Centres do not. drug-related is not the same in all cases, (iii) that the information does not represent the opinion The volume of reports for a particular medicinal product may of the World Health Organization. be influenced by the extent of use of the product, publicity, the nature of the reactions and other factors. No information is Omission of this statement may exclude the responsible provided on the number of patients exposed to the product. person or organization from receiving further information from VigiBase.

2011

WHO Pharmaceuticals Newsletter No. 2, 2014  29