Danish Pharmacovigilance Update Celebrates Its 4Th Anniversary Page 17

DanishDanish Pharmacovigilance Pharmacovigilance Update # 1

Update 10Year 4 28 November 2013

Contents

News from the EU

Acipimox (Olbetam®) should only be used to lower triglycerides when other page 2 treatments of dyslipidaemia are not sufficient

Risk of blood clots from the use of the cancer medicine ponatinib (Iclusig®) page 3

All patients should be screened for hepatitis B virus (HBV) before starting page 4 treatment with rituximab (Mabthera®)

Preparation error resulting in overdose of cabazitaxel (Jevtana) page 5

News from the Danish Health and Medicines Authority

Ciprofloxacin and the risk of tendon disorders page 6

Decrease in the use of medicines for the treatment of anogenital warts page 7 in adolescents under the age of 20 page 9 Bisphosphonates/denosumab and the risk of osteonecrosis of the jaw page 12 The tugboats of preventive health – an article from the Danish weekly newspaper Weekendavisen

Short news

Batches of the NovoMix®30 FlexPen® recalled page 15

Reporting of adverse reactions to the Danish Health and Medicines Authority page 16

Danish Pharmacovigilance Update celebrates its 4th anniversary page 17

Danish Pharmacovigilance Update – Newsletter from the Danish Health and Medicines Authority Danish Pharmacovigilance Update Status on Eltroxin® following change in excipients 2

News from the EU

Acipimox (Olbetam®) should only be used to lower triglycerides when other treatments of dyslipidaemia are not sufficient

The European Pharmacovigilance Risk an additional reduction of the risk of and acipimox has only shown effect on Assessment Committee (PRAC) has serious vascular events as compared lipid changes (primarily triglycerides) reviewed data on the efficacy and safety with statins alone, but did result in and not on changes in cardiovascular of the nicotinic acid analogue acipimox, an increased risk of serious adverse morbidity or mortality. which is used for the treatment of reactions. dyslipidaemia. On this basis, the PRAC concluded Recent assessment does not give that acipimox may stay on the market The withdrawal of a combination cause to suspension of acipimox as an adjunctive or alternative treatment product containing nicotinic acid According to the assessment, the for lowering triglycerides. However, formed the basis for a new results of the study cannot be directly acipimox should only be used when assessment of acipimox extrapolated to acipimox, partly because changes in lifestyle and treatment with The reason for the review is the the study concerned combination other medicines such as statins and withdrawal of the medicine Tredaptive® treatment so that it is not possible to fibrates alone have not been sufficient. at the beginning of 2013. Tredaptive® distinguish between the efficacy of contained a combination of nicotinic the two substances, partly because of For further information, please read acid and laropiprant and was withdrawn potential differences between nicotinic the EMA's press release. when a large study1 into the effect of acid and the analogue acipimox. PRAC recommends using acipimox only supplementing statins with nicotinic However, the overall data for acipimox as additional or alternative treatment to acid/laropiprant indicated that the are very limited as compared with data lower high triglyceride levels. adjunctive treatment did not lead to on other available treatment options,

1 HPS2-THRIVE: Heart Protection Study 2 – Treatment of HDL (high density lipoprotein) to Reduce the Incidence of Vascular Events.

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News from the EU

Risk of blood clots from the use of the cancer medicine ponatinib (Iclusig®)

The committees of the European Until further notice, ponatinib Medicines Agency, EMA, are currently may be used within the approved reviewing new information about indication provided the following Indication for Iclusig® the risk of blood clot related events is observed: associated with the tyrosine kinase • Ponatinib may not be used in patients Iclusig® is indicated for the inhibitor ponatinib (Iclusig®). with a history of myocardial infarction treatment of adult patients with: or stroke, unless the potential benefits Approved indication of treatment are assessed to outweigh • Chronic phase, accelerated Ponatinib is approved for the treatment the risk. phase, or blast phase chronic of chronic myeloid leukaemia (CML) myeloid leukaemia (CML), and for patients with particular types • The cardiovascular treatment who are resistant to dasatinib of acute lymphoblastic leukaemia should be optimised before starting or nilotinib, who are intolerant (ALL). The risk of blood clots has treatment with ponatinib, and the to dasatinib or nilotinib and for been known and described in the cardiovascular status should be whom subsequent treatment product information since the approval monitored and optimised continuously with imatinib is not clinically of ponatinib in July 2013. Since its during treatment. appropriate, or who have the approval, ponatinib has been limited to T315I mutation. use in patients who could not be treated • Hypertension should be well-controlled with other tyrosine kinase inhibitors. during treatment with ponatinib and • Philadelphia chromosome discontinuation of the treatment should positive acute lymphoblastic Need for a new assessment of be considered if the hypertension leukaemia (Ph+ ALL), who benefits and risks of the medicine cannot be controlled. are resistant to dasatinib, However, the new data show that the who are intolerant to dasatinib risk of cardiovascular events, including • Patients should be monitored closely and for whom subsequent blood clots, may be higher than assessed for symptoms of blood clot related treatment with imatinib is not earlier. Therefore, a thorough assessment events, and the treatment should clinically appropriate, or who of the benefits and risks of the medicine be interrupted immediately if such have the T315I mutation. is necessary. symptoms occur.

For further information, please read the EMA's press release. European Medicines Agency recommends changes in use of leukaemia medicine Iclusig (ponatinib) in order to minimise risk of blood clots.

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News from the EU

All patients should be screened for hepatitis B virus (HBV) before starting treatment with rituximab (Mabthera®)

Based on a recent analysis, the New recommendations for doctors: The product information for MabThera® Committee for Medicinal Products has been updated, and letters with this for Human Use (CHMP) under the • All patients (not just those at risk of new recommendation have been issued European Medicines Agency, EMA, HBV infection) should be screened to relevant doctors. See the letter on the has decided that all patients – not for HBV before starting treatment Danish Health and Medicines Authority's just those at risk of HBV infection – with rituximab within all indications website: List of issued DHPC letters should be screened for HBV before (in Danish only). starting treatment with rituximab. • Patients with active hepatitis B disease should not be treated HBV reactivation has been reported with rituximab in persons with positive hepatitis B surface antigen (HBsAg) and in persons • Patients with positive hepatitis B Indication for MabThera® with positive core antibody (anti-HBc), serology should be referred to a Non-Hodgkin’s lymphoma, even when HBsAg was negative – liver disease expert before starting chronic lymphocytic leukaemia, particularly when administering treatment with rituximab. These rheumatoid arthritis, granuloma rituximab in combination with steroids patients should be monitored and tosis with polyangiitis and or chemotherapy. managed to prevent HBV reactivation microscopic polyangiitis. during treatment. There are reports of cases of fulminant hepatitis, some of which were fatal.

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News from the EU

Preparation error resulting in overdose of cabazitaxel (Jevtana)

In the EU, Jevtana overdose events the solvent is more than the content Letters with the above-mentioned resulting in serious adverse reactions stated on the vial – the content stated information have been issued to the including bone marrow suppression is the nominal value (4.5 ml) and not hospital pharmacies and to relevant have been reported. The overdose events the actual value (5.67 ml). doctors. See the letter on the DHMA's resulted from a preparation error due website: List of issued DHPC letters to which the actual dose was 15-20% Risk in case of overdose (in Danish only). higher than the prescribed dose. The anticipated complications of overdose are exacerbation of adverse The summary of product characteristics Also in Denmark, Jevtana overdose reactions such as bone marrow will be updated to ensure that the events have been reported. suppression and gastrointestinal guidelines concerning preparation disorders. of Jevtana cannot be misunderstood. Be aware of the dosage when In addition, initiatives to minimise the preparing Jevtana Special precautions when using risk of future errors are being prepared. Cabazitaxel is supplied as a vial of an automated software system concentrate and a vial of solvent. in the preparation Jevtana is included in the EU list of The concentrate must first be diluted When using an automated software medicines under additional monitoring. with the solvent supplied to a system in the preparation, it must be concentration of 10 mg/ml before ensured that the system is set up to adding to the infusion solution. allow withdrawal of the entire content of the solvent vial for adding to the The vials each contain an overfill to concentrate vial in order to ensure Indication for Jevtana compensate for liquid loss during a concentration of 10 mg/ml. Jevtana is indicated in preparation. This means that the combination with prednisone or dose in each vial is higher than the The marketing authorisation holder prednisolone for the treatment dose stated on the vial. has informed the Danish Health and of metastatic hormone-refractory Medicines Authority (DHMA) of yet prostate cancer (mHRPC) in Therefore, it is very important to another preparation error where the patients previously treated with transfer the entire content of the weight entered into the automated a regimen containing docetaxel. solvent to the concentrate in order software systems is the value stated to obtain the correct concentration on the vial of concentrate (60 mg) and of cabazitaxel. The entire content of not the actual weight in the vial (73.2 mg).

Danish Pharmacovigilance Update – Newsletter from the Danish Health and Medicines Authority Danish Pharmacovigilance Update Status on Eltroxin® following change in excipients 6

News from the Danish Health and Medicines Authority

Ciprofloxacin and the risk of tendon disorders

In September, the Danish Health and Doctors should pay attention to the use of quinolones. However, Medicines Authority (DHMA) received the following: in very rare cases ciprofloxacin may an adverse reaction report concerning be prescribed for the treatment of an elderly man who developed pain in • Even within the first 48 hours after certain serious infections following one of his Achilles tendons eight days starting treatment with ciprofloxacin, microbiological documentation of after starting treatment with ciprofloxacin tendinitis and tendon rupture the causal organism and an for pneumonia. The tendon turned out (in particular involving the Achilles assessment of the risks and benefits. to be partially ruptured. The patient is tendon) may occur, sometimes This mainly applies if the standard currently in recovery. bilaterally. Even several months treatment has failed or in case of after completing the treatment with bacterial resistance where the Reports of tendon disorders ciprofloxacin, inflammation and microbiological data justify the use in association with the use of tendon ruptures may occur. The risk of ciprofloxacin. ciprofloxacin of tendinopathy is higher in elderly The DHMA has received a total of 33 patients and in patients in concomitant • Caution should be used when reports of tendon disorders suspected treatment with corticosteroids. prescribing ciprofloxacin to patients to be adverse reactions from the use of with myasthenia gravis. ciprofloxacin. In the reports, the adverse • At the first sign of tendinitis (e.g. reactions are described as tendinitis, painful swelling or inflammation), See the indication for ciprofloxacin tendon rupture, tendon pain, tendon ciprofloxacin should be in Danish at: www.produktresume.dk. injury etc. discontinued. Note: The DHMA recommends to • In general, ciprofloxacin should not limit the consumption of this antibiotic, be used in patients with a history of see the DHMA's Guidelines on prescribing tendon disorders associated with antibiotics.

All cases referred to in the article originate from the Danish Health and Medicines Authority's adverse reaction database. The cases have been forwarded to all relevant pharmaceutical companies and to the EudraVigilance database. Therefore, pharmaceutical companies should not report these cases to the Danish Health and Medicines Authority.

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News from the Danish Health and Medicines Authority

Decrease in the use of medicines for the treatment of anogenital warts in adolescents under the age of 20

In June 2013, a Danish study was published electronically in the journal 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 ”Clinical Infectious Disease”. The study 14 years 23 30 26 30 34 40 22 14 19 11 showed that the vaccine against human 15 years 47 78 88 99 112 141 120 49 42 27 papillomavirus (HPV) had a good effect on anogenital warts in girls. Another 16 years 120 169 191 238 308 373 285 129 62 41 Danish study published in the ACTA 17 years 236 293 344 413 519 608 657 395 160 82 Dermato-Venereologica in October 18 years 376 400 494 572 723 909 1000 768 409 153 2013 also showed a reduction in the 19 years 503 568 722 790 880 1089 1208 1026 840 438 incidence of anogenital warts in boys, In total 1305 1538 1865 2142 2576 3160 3292 2381 1532 752 particularly in young boys under the age of 201. Figures from the Statens Serum Institut, National Institute for Table 1. The number of adolescents under the age of 20 who redeemed a prescription for Health Data and Disease Control, at podophyllotoxin. www.medstat.dk support these results when looking at the use of medicines for the treatment of anogenital warts. 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 14 years 8 13 7 9 8 15 19 10 6 6 Antiviral medicines containing 15 years 11 11 10 15 17 18 19 7 1 3 podophyllotoxin (Condyline® and Wartec® (dereg. Sept. 2012)) or 16 years 5 8 15 13 20 24 22 10 4 3 imiquimod (Aldara®) are used for 17 years 12 12 21 24 27 27 32 28 9 14 medical treatment of anogenital warts. 18 years 23 17 27 36 61 39 45 44 22 11 The medical treatment must be initiated 19 years 15 20 40 44 46 74 74 51 48 24 with podophyllotoxin, which is also In total 74 81 120 141 179 197 211 150 90 61 used more frequently than the other active substance on the market. The consumption of podophyllotoxin Table 2. The number of adolescents under the age of 20 who redeemed a prescription for imiquimod. in adolescents under the age of 20 increased significantly until 2009, after which the trend reversed. Table 1 childhood immunisation programme boys aged 12-26 years were vaccinated2, shows that the number of adolescents as of 1 January 2009. so the large drop in the consumption under the age of 20 who redeemed a in boys may indicate that the risk of prescription for this medicine was In adolescents under the age of 20 infection decreased. 3,292 in 2009, and in just three years there is also a significant drop in the the number decreased to 752. consumption of the less frequently The significant drop in the consumption Accordingly, the number of users used medicine Aldara (imiquimod) of the antiviral medicines for the of this antiviral medicine in this (Table 2). treatment of anogenital warts may be population was reduced by 77%. explained by other factors including There is a temporal association between The significant drop in the consumption the more frequent use, in recent years, the significant drop in the consumption of podophyllotoxin is seen in both boys of alternative treatment methods such and the introduction of the HPV vaccine, and girls with figures of 71% and 81%, as freezing, surgery or laser therapy. which was included in the Danish respectively, during the period 2009 to However, when looking at the 2012 (Figure 1). Only approx. 1% of the consumption of the antiviral medicines

1 Sandø N, Kofoed K, Zachariae C, Fouchard J. A Reduced National Incidence of Anogenital Warts in Young Danish men and Women after Introduction of a National Qaudrivalent Human Papillomavirus Vaccination Programme for Young Women – An Ecological Study. 2 http://www.ssi.dk/Aktuelt/Nyheder/2013/2013_11_HPV-vaccinerede%20drenge.aspx (in Danish only)

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News from the Danish Health and Medicines Authority

in other age groups, the drop is much less significant than in the young adolescents under the age of 20, see Figure 2. Data on the participation in vaccination for the HPV vaccine show that approx. 80-90% of all girls born during the years 1993 to 1999 have received all three doses of the vaccine3. Number of boys Number For girls and women who are to pay for Number of girls the vaccine themselves, the coverage is much lower (<30% for at least 1 dose)4.

Published studies and consumption figures already indicate that the introduction of the HPV vaccine in Year the Danish childhood immunisation programme has had a good effect on Figure 1. The number of girls and boys under the age of 20 who redeemed a prescription for the prevention of anogenital warts. The podophyllotoxin. effect of the vaccine is detectable this early, because the incubation time for anogenital warts is 3 months on average.

14-19 years 20-24 years

Number 25-29 years

3 http://www.ssi.dk/Smitteberedskab/ 30-34 years Sygdomsovervaagning.aspx (in Danish only) 35-39 years 4 Maria Blomberg, Christian Dehlendorff, Christian Munk and Susanne K. Kjaer. Strongly Decreased Risk of Genital Warts After Vaccination Against Human Papillomavirus: Year Nationwide Follow-up of Vaccinated and Unvaccinated Girls in Denmark. Clinical Figure 2. The number of persons in the age groups under the age of 20, 20-24 years, 25-29 years, Infectious Disease 2013; 57 (7): 929-34. 30-34 years, respectively, who redeemed a prescription for podophyllotoxin.

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News from the Danish Health and Medicines Authority

Bisphosphonates/denosumab and the risk of osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is a AmountAmount sold sold of bisphosphonates and and denosumab denosumab in inthe the hospital hospital sector. sector. serious bone disease associated with pain and inflammation and, potentially, 2400 infection and fistula formation secondary 2100 to exposure of the bone tissue. 1800 Etidronic acidacid Recently, the Danish Health and 1500 Medicines Authority (DHMA) has Pamidronic acid received several adverse reaction 1200 Alendronic acid reports concerning osteonecrosis 900 Ibandronic acid of the jaw in association with the Risedronic acid use of bisphophonates. 600 Risedronic acid Amount sold in 1,000 units

The topic has been described earlier in Amount sold in 1,000 units Zoledronic acid 300 Danish Pharmacovigilance Update 18 Denosumab February 2010. However, due to a high 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 number of new reports and an increasing consumption of bisphosphonates and Year denosumab, the DHMA has once again reviewed risk factors and preventive Figure 1. Bisphoshonates and denosumab sold, in DDD, in the hospital sector during the period measures. 2004 through 2012. Source: The Danish Register of Medicinal Product Statistics, at the Statens Serum Institut, National Institute for Health Data and Disease Control. Danish adverse reaction reports concerning ONJ During the period January 2004 to July Number of persons who redeemed at least one prescription for 2013, the DHMA received 95 reports bisphosphonates and denosumab, in the primary care sector. concerning ONJ in association with the 100.000 use of bisphophonates or denosumab. The majority of the reports concern 90.000 cancer patients, but a few reports 80.000 concern patients with osteoporosis. 70.000 Etidronic acid

Consumption of bisphosphonates 60.000 Pamidronic acid and denosumab1 in the hospital 50.000 and primary care sectors Alendronic acid Figure 1 shows that the sale of ibandronic 40.000 Ibandronic acid Number of persons acid increased from 234,000 units in 30.000 Risedronic acid 2004 to 1.7-2 million units in 2009, after which the sale did not increase any 20.000 Zoledronic acid further. This makes ibandronic acid Denosumab 10.000 the best selling bisphosphonate in the

hospital sector, even though the sale 0 2004 2005 2006 2007 2008 2009 2010 2011 2012 of denosumab, which was approved in 2010, also increased considerably over Year the past year. Ibandronic acid and denosumab are used in the hospital Figure 2. Number of persons who redeemed at least one prescription for biphoshonates or denosumab sector for the treatment of osteoporosis in the primary care sector during the period 2004 through 2012. Source: The Danish Register of and prevention of skeletal-related Medicinal Product Statistics, the Statens Serum Institut, National Institute for Health Data and Disease Control. 1 The list of bisphosphonates and products containing denosumab, marketed in Denmark, is shown in the box.

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News from the Danish Health and Medicines Authority

events in cancer patients. Furthermore, ibandronic acid, clodronate and Bisphosphonates marketed in Denmark: pamidronate are used in the treatment of hypercalcaemia caused by tumours. Treatment of osteoporosis: Zoledronic acid is indicated for Paget's Aclasta® (zoledronic acid)(also indicated for disease of the bones. the treatment of Paget's disease of the bones) Solution for infusion In Denmark, ibandronic acid and Alendronate, Bonasol® (alendronate) Tablets zoledronic acid are marketed as solutions Fosama® (alendronate) Weekly tablet for infusion that are mainly used in the Fosavanc® (alendronate, cholecalciferol) Tablets hospital sector. Ibandronic acid is also ® marketed as tablets, which explains Bonviva (ibandronic acid) Tablets the use in the primary care sector for Ibamyl, Ibandronat, Ibandrostad (ibandronic acid) Tablets the treatment of osteoporosis. Didronel (etidronate) Tablets Optinate® Septimum, Risedronate sodium, Figure 2 shows the sale pattern for the Risostad (risedronate) Tablets primary care sector which, as expected, Treatment of hypercalcaemia: differs from the pattern for the hospital sector. In the primary care sector, the Zoledronic acid (zoledronic acid) Solution for infusion sale share for denusomab is very small Bondronat®, Iasibon (ibandronic acid) Solution for infusion with 4,650 redeemed prescriptions in Bonefos (clodronate) Tablets 2012 vs. 87,272 prescriptions redeemed Pamidronate disodium (pamidronate) Solution for infusion for alendronic acid/ alendronate. The number of prescriptions redeemed for alendronate increased throughout the period from 2004 up until 2013, whereas a decrease was observed in the number of prescriptions redeemed Products containing the active substance denosumab, marketed in for etidronic acid/ etidronate. Ibandronic acid/ ibandronate, which Denmark: dominate the sale in the hospital sector, Treatment of osteoporosis and prevention of skeletal-related events in only comprise a small part of the sale adults with bone metastases from solid tumours: in the primary care sector with just Prolia (denosumab) Injection fluid below 6,000 redeemed prescriptions in Treatment of osteoporosis and bone loss caused by 2012 – a consumption which has been hormone ablation or bilateral orchiectomy in case of prostate cancer: fairly stable since 2008. Ibandronate is marketed as both tablets and solution Xgeva (denosumab) Injection fluid for infusion. This explains the use in the primary care sector for the treatment of osteoporosis. Denosumab is marketed exclusively as solution for infusion. high when treating cancer patients • Concomitant or previous treatment with either bisphosphonates or with corticosteroids, chemotherapy, The sale of zoledronic acid/ zoledronate, denosumab2. antiangiogenic treatment or head risedronic acid/ risedronate and pami and neck radiotherapy. dronic acid/ pamidronate is small in Other known risk factors for ONJ are: • Local dentoalveolar surgery. both sectors. • Cancer with bone lesions. Preventive measures to minimise Risk factors for the development • Treatment with the most potent the risk of ONJ described in the of ONJ bisphosphonates (e.g. zoledronate). summary of product characteristics A recent meta-analysis has shown that • Intravenous administration of All the summaries of product the risk of developing ONJ is equally bisphosphonates. characteristics for bisphophonates

2 Prashanth Peddi et al 2013 3 CHMP assessment report on bisphosphonates and osteonecrosis of the jaw 2009.

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and denosumab specify the risk of • The patient must inform the dentist developing ONJ and possible preventive about any medical treatment – measures. Retrospective studies have including use of bisphosphonates or shown that the risk of ONJ is decreased, denosumab, so that the dentists can if the patients, prior to initiation of take possible precautions against ONJ treatment with bisphosphonates or denosumab, get a dental check-up • The patient should, whenever and complete any dental treatments possible, complete major dental and if the administration intervals for treatments prior to initiating intravenous treatments are increased3. treatment with bisphosphonates or denosumab, and the patient should Prescribing doctors should direct the dentist's attention to the provide the following ongoing treatment with these instructions to the patient: medicines, in case major dental treatments become necessary • The importance of being particularly during such ongoing treatment. careful about oral hygiene • Discontinuation of the treatment • The patient must contact his or with bisphosphonates or denosumab her dentist as soon as possible prior to a dental treatment will not to prepare a plan for preventive reduce the risk of ONJ. examinations and treatment, for example including scheduling more frequent examinations or regular fluoride treatment, if deemed necessarily

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Danish Pharmacovigilance Update here brings an article from the Danish weekly newspaper Weekendavisen of 25-31 October 2013.

Lately, the HPV vaccine Gardasil® has been debated in various media, and the Danish Health and Medicines Authority's (DHMA's) work of monitoring the vaccine and the status of the adverse reaction reports have been described in Danish Pharmacovigilance Update. Most recently, the newspaper Weekendavisen featured a front page article entitled 'The tugboats of preventive health' that puts the entire debate on the HPV vaccine and vaccination in general into perspective. Therefore, we have chosen to include the article in this issue of Danish Pharmacovigilance Update.

The tugboats of preventive health By Lone Frank

There is no shortage of online warnings 'And it really is of practical importance', Americans presented impressive new for young girls. 'Remember that we says David Hawkes, Molecular Virologist data on its efficacy.' will start a new round of stories about and vaccine researcher at Melbourne's Gardasil and Cervarix next week' is a Florey Institute. In June, a group from the American statement shared with the Facebook Centers for Disease Control published group ‘HPV Vaccine’ by a man who For instance, vaccine opposition has a study which shows that the vaccine calls himself Chandler Marrs. And resulted in the return of diseases such halved the number of HPV infections continues: 'When you share your story, as measles and pertussis in certain in young girls in the USA between it makes others hesitate to get the Western countries and the current 2006 and 2010. This decrease occurred vaccine. Thank you.' While you are spread of the life-threatening polio even though only a third of the American waiting for the personal stories, a furious in several developing countries. teenage girls receive the full vaccine woman shares a new scientific study dose of three injections and exceeds from British Medical Journal. Based 'The reasons for the vaccine opposition the researchers' expectations. In the on data from a million Scandinavian are numerous and complex. But it wake of the publication, the New York adolescents, the article rejects that the seems as if we are dealing with a sort Times features a series of articles about vaccine, which is aimed at protecting of scapegoat in the healthcare area. the HPV vaccine and its assumed ability against infection with the HPV virus The general dissatisfaction has increased to prevent not only cervical cancer, but responsible for 70 percent of all cases and has been directed towards vaccines also virus related neck cancer in both of cervical cancer, causes serious to a degree that triggered a protest’. men and women. In a leading article, adverse reactions. The comment on says Hawkes and counts on his fingers: the newspaper even concludes that: Facebook is as follows: 'Bullshit!' 'There is dissatisfaction with the 'Doctors should recommend and parents pharmaceutical industry, uncertainty should accept a vaccine which can Vaccines constitute an interesting field. as regards the role of the medical save thousands of lives.' Their position as one of the greatest establishment vs. the industry and, health advances of mankind cannot in some places, a basic aversion to So why do the Japanese withdraw their be rejected, and they have saved anything emanating from the authorities.' recommendation? unnumbered millions from diseases, their complications and, ultimately, Symptoms and cause 'Traditionally, they are extremely careful death. The American epidemiologist Hawkes spent most of his summer on when it comes to vaccinations', says and strategist behind the eradication debating the HPV vaccine. He went Hawkes. 'The vaccine is still available, of the smallpox virus, William Foege, into action when a discussion about and the authorities consider it safe. has referred to the vaccines as 'the potential serious adverse reactions However, due to an ongoing detailed tugboats of preventive health'. Still, rekindled in several countries following review of potential adverse reactions they continue to be a controversal topic. the withdrawal of the Japanese health they refrain from recommending actively.' One can hardly imagine a movement authorities' official recommendation of fighting persistently against the use of the vaccine. The fact of the matter is that 1,968 cholesterol-lowering medicines or potential serious adverse reactions psychotropics, whereas many countries 'We were in the middle of a paradox', have been reported in Japan, a country harbour an actual anti-vaccination lobby. says Hawkes. 'The attacks on the vaccine came at a time when the

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News from the Danish Health and Medicines Authority

in which 3.3 million women have received the DHMA in the most recent issue was used globally in 2009, but is under HPV vaccination. Various symptoms of Danish Pharmacovigilance Update, suspicion for causing the rare neurolo ranging from heart palpitations and it is impossible to determine a possible gical disorder narcolepsy in approximately fainting to severe chronic pain. So far, causal relationship without a diagnosis. 300 children in Finland and Sweden. 43 cases have been investigated by a task force in the Japanese Ministry of 'I have no doubts that this is a specific 'These are the only countries with an Health, but it hasn't found any evidence HPV syndrome', says Else Jensen who increased incidence of the disorder of a correlation with the vaccine. is now focusing on having the vaccine among vaccinees, and Finnish immunolo The same pattern applies in the USA, withdrawn. 'And my judgement is based gists are working on shedding light on as pointed out by Hawkes and two on some patterns I see. The women the mechanism. The theory is that another colleagues in a thorough review of the have reactions from three major areas virus circulated at the time of the available data in the most recent issue – the immune system, the hormonal vaccination and impacted on the of the journal Infectious Agents and system and the nervous system – and I children's immune system', says Mølbak Cancer. In the USA, among the 111 do not at all believe that the symptoms and stresses that 'there should certainly million doses given, potential serious could be randomly occurring.' be room for an open debate on vaccines'. adverse reactions have been reported in 0.03 percent, i.e. three in ten thousand. Put off with talk There are indications that an actual However, as emphasised by Hawkes: Jan Pravsgaard Christensen, debate with the organised vaccine 'A causal relationship has not been Professor of Immunology at the criticism may be difficult. Mainly shown in any cases.' University of Copenhagen, refer to the because the Internet and the social specific criticism of the HPV vaccine media provide opportunities to both This does not quieten critical as 'unscientific'. And at the same time, come together and to isolate oneself. organisations such as the Danish he calls attention to a general issue in This is seen already in the earliest VaccinationForum. the vaccine debate. 'Every time you ask study of the phenomenon published for documentation from various vaccine in the Journal of Medical Internet 'They are just doing an estimate of the critical organisations, you are put off Research in 2005, where researchers likelihood of causality and not a clinical with talk. The media allow them to from the Pittsburgh School of Medicine examination of the injured persons', deliver anecdotes and cast a general analysed hundreds of websites and says Chairman, Nurse Else Jensen. suspicion, whereas I, as a researcher, found clear patterns. First, 'serious She threw herself into the Danish have to provide solid documentation. accusations' are put forward, typically discussion of the HPV vaccine which I'm typically asked to guarantee that referring to a vaccine as a trigger of a was launched in the middle of the a given vaccine is not the cause of disease. Examples are autism, summer silly season. Two young girls symptoms in a given patient.' sclerosis and cot death. The next step with tears in their eyes as they were is to blacken the reputation of vaccine seen on TV describing their chronic Obviously, that kind of guarantees advocates in general and, finally, the suffering which, according to the girls, are impossible to give. As stressed by websites are linked to each other to most definitely was caused by the Kåre Mølbak, Consultant Doctor and an extreme degree thereby creating an vaccine. The symptoms are general – Head of Department at the Statens echo chamber where people can move muscle and joint pain, dizziness, Serum Institut, National Institute for in peace and confirm each other. fatigue – and even though no doctor Health Data and Disease Control, has been able to identify any disease no vaccines are free of risks or adverse 'There are several types of underlying at this point, the media quickly went reactions. 'The purpose is to stimulate motivations in the vaccine criticism', into overdrive. As claimed by the the immune system, and people are says anthropologist Ayo Wahlberg. Danish newspaper BT in a headline: not physiologically alike. There will always As associate professor at the University '400,000 girls in danger: The HPV be individuals who develop an unfortunate of Copenhagen, he participates in a major vaccine may cause serious adverse and inappropriate immune reaction.' mapping of scientific controversies, reactions.' where, among other things, the HPV And the reason for monitoring vaccine will be scrutinised. 'We are Following the press coverage, the Danish vaccines continuously is to detect looking at a group of people who have VaccinationForum was flooded with potential effects that may appear in chosen a critical approach to mainstream communications, and so far 25 women connection with widespread use or medicines and swear by alternatives. have reported similar diffuse symptoms unforeseen local circumstances. They typically consider vaccination to the DHMA. Here, all reports are The latter was seen with the vaccine another example of 'harmful chemistry' assessed. However, as described by against H1N1 influenza, Pandemrix, which that we put into our bodies.”

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However, as soon as an actual debate that in a tuna sandwich', states David Pravsgaard Christensen continues: rekindles, it becomes clear, according to Hawkes. 'And when thimerosal was 'I believe that the opposition has much Wahlberg, that something more is at stake. removed from the vaccine there was no to do with the fact that we do not subsequent decrease in the number of experience the effect of a vaccine. 'The essence is uncertainty in the autistic children. But the myth lives on.' You won't notice that you avoided a professional debate. Discussions disease, and today entire generations that used to be held behind the Despite the fact that Andrew Wakefield are thoroughly vaccinated and have closed doors of medical conferences, has been deprived of the right to practise grown up without childhood diseases.' are now conducted in the media and and that his results have become are apparent to all of us. The uncertainty thoroughly discredited following the And Mølbak adds: 'When a vaccine works with regard to vaccines emanates from Lancet's withdrawal of the original so well that a given disease disappears, always facing a number of potential article, as it turned out to comprise people only see the adverse reactions adverse reactions, but never really being highly selective and even fabricated of the vaccine. That way the success of able to identify a causality. Also, our risk data. Those steps were taken in 2010, vaccines is almost their own worst enemy.' tolerance is generally very low. You need and the following year an article in the to act on every risk. Otherwise you are Annals of Pharmacotherapy termed HOWEVER, only almost, since there disengaged. So you search out a dissident the entire MMR case: 'The most harmful are worse enemies out there. There are in the scientific environment and make medical swindle of the past hundred indications that the deadly polio virus, that person's statements the main focus years.' Harmful, since it resulted in a which causes infantile paralysis, may of your criticism and opposition.' decrease in the vaccination coverage spread again due to political and among young children in several Western religious opposition to vaccination. The vaccine against measles countries. The greatest impact occurred A good example is the most 'successful' in the UK, where a drop from 92 to 73 In Nigeria, where the virus is endemic, anti-vaccine campaign to date, which per cent, and in certain parts of London conservative Muslim leaders started has been conducted against the so-called to only 50 per cent, was observed around encouraging a boycott of polio MMR vaccine for a good ten years. Given the turn of the millennium. Since then, vaccination of children in 2001, since to young children to protect against the UK as well as the USA and the they believe that it is a Western plot measles, mumps and rubella, the vaccine Netherlands have experienced epidemics aimed at sterilising Muslims. The state was correlated to autism by the British of particularly measles with associated Kano suspended vaccination for months, doctor Andrew Wakefield. He did so in complications and a few deaths. and the disease spread to neighbouring 1998 with a study published in the Lancet, countries where it had previously been and even though it was based on just 12 In Norway and Sweden the vaccination eradicated. Also, since that time, children, the British media succeeded coverage is still above 95 per cent, Nigeria itself has experienced several in creating an atmosphere of uncertainty whereas it has decreased to 90 per outbreaks with considerable numbers that spread internationally. Major studies cent in Denmark. And that is actually of deaths. As recently as February, on, for example, Scandinavian data too low for us to expect flock immunity healthcare workers who tried to contradicted the statements very clearly, to measles virus. This means that the dispense vaccine were shot in Kano. but did not permeate through the often number of vaccinees is not sufficient personal and emotional noise. to prevent spreading of infection among Currently, the situation is the same the non-vaccinees, in case it should occur. in the northern part of Pakistan where In the USA, science, among other the tribal regions of Waziristan are things, was up against the model 'People should realise that they opt for experiencing an outbreak of polio. and mother of an autistic son, a risk for their children by opting out Based on the same grounds as in Jenny McCarthy, and the organisation of vaccination', as emphasised by Jan Nigeria, the local Taliban is making an Generation Rescue, both keen on Pravsgaard Christensen. 'If they get energetic attempt to prevent vaccination pushing parents towards refraining ill from childhood diseases, they may of children, and both healthcare from having their children vaccinated also suffer from complications, and professionals and the police, who are then and now. They and other activists perhaps they will contract these diseases charged with protecting them, have have typically pointed out that the in adulthood where the complications been killed. So far, the Taliban action is vaccine contained the mercury-based are particularly serious.' believed to have cost dozens of children additive thimerosal. Rubella in pregnant women will result their mobility, and sewage water tests in abortion, and mumps in adult men in several major cities in Pakistan have 'Actually, the content of mercury in a can make them sterile. shown that the virus has started sprea dose of MMR vaccine was lower than ding in regions that used to be free of it.

Danish Pharmacovigilance Update – Newsletter from the Danish Health and Medicines Authority Danish Pharmacovigilance Update Status on Eltroxin® following change in excipients 15

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Batches of the NovoMix®30 FlexPen® recalled

A manufacturing fault in batches of NovoMix®30 FlexPen® – faulty the insulin medicine NovoMix®30 batches: FlexPen®, which contain too much or NovoMix® is an insulin too little insulin, may lead to an Product number: 006024 product used for the treatment increased risk of hypoglycaemia or of diabetes. The active substance hyperglycaemia. Batch no. and expiry: in NovoMix® is insulin aspart. CP51098 10/2014 NovoMix® is available in Therefore, the marketing authorisation CP50915 10/2014 pre-filled pens (FlexPen®) and holder, Novo Nordisk, has recalled CP50412 07/2014 cartridges (Penfill®). specific batches of NovoMix®30 FlexPen® from wholesalers, pharmacies and NovoMix®30 contains 30% patients. Product number: 500814 rapid-acting insulin aspart and 70% intermediate-acting Only a few faulty batches Batch no. and expiry: insulin aspart. Information from Novo Nordisk shows CP50904 10/2014 that only 0.14% of the cartridges contain CP50650 07/2014 In Denmark, an estimated an incorrect amount of insulin. However, CP51097 10/2014 number of approx. 15,000 in the pens affected, the content of CP50641 07/2014 patients receive treatment insulin may vary from 50% to 150% of with NovoMix®30 FlexPen®. the number of insulin units specified. Product number: 016361 The other strengths of Advice for doctors: NovoMix® are not affected Batch no. and expiry: by the manufacturing fault. • As soon as possible, patients using CP5109500 10/2014 the batches of NovoMix®30 FlexPen® CP5090400 10/2014 affected should be switched to batches CP5090401 10/2014 that are not affected by the recall, or CP5090402 10/2014 – if not possible – to another treatment. CP5090403 10/2014 CP5065000 07/2014 Patients should be encouraged CP5065001 07/2014 to check the batch number / lot CP5064100 07/2014 number of their NovoMix®30 FlexPen®.

Danish Pharmacovigilance Update – Newsletter from the Danish Health and Medicines Authority Danish Pharmacovigilance Update Status on Eltroxin® following change in excipients 16

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Reporting of adverse reactions to the Danish Health and Medicines Authority According to Danish executive order It is important to report all The best possible patient safety no. 826, doctors have an obligation to adverse reactions to the DHMA. The deadline of 15 days was established report all serious1 adverse reactions The DHMA receives and records all in the Danish executive order to ensure to the Danish Health and Medicines reports of suspected adverse reactions. that the DHMA is informed about Authority within 15 days from suspecting This also applies to reports of any suspected serious adverse reactions their existence. Furthermore, doctors have suspected serious adverse reactions as soon as possible and that the an obligation to report all unexpected submitted later than 15 days from the DHMA this way is provided with the adverse reactions and all adverse doctor's suspicion of them. best possible basis for reacting quickly reactions caused by new medicines, to new and important knowledge of i.e., medicines that have been on the The DHMA is aware that systematised potential adverse reactions. market for less than two years. retrospective reviews of medical records are conducted from time to The obligation to report within 15 days time to identify particular diagnoses for serious adverse reactions thus emerged in association with a given applies from the time when the doctor treatment. Also in such cases is it suspects the existence of the adverse important to submit a report, even if reaction and not from the time of onset a correlation between the diagnosis of the adverse reaction in the patient. and the medicine used for treating In some cases, suspicion of an adverse the patient is only suspected. reaction in a patient will be somewhat delayed – and sometimes it may arise several years after the patient's experience of the adverse reaction. These adverse reactions must also be reported to the DHMA.

1 An adverse reaction is serious, if it: • is fatal • is life-threatening • causes or prolongs hospitalisation • causes persistent or significant disability or incapacity • causes foetal defects or congenital anomaly.

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Danish Pharmacovigilance Update celebrates its 4th anniversary

In November 2009, the first issue of Danish Pharmacovigilance Update, We are very pleased that the newsletter Danish Pharmacovigilance Update 27 June 2013, Danish Pharmacovigilance continues to attract strong interest and was released. This means that this Update, 29 August 2013, Danish positive response, and we hope that it year we are celebrating the 4th Pharmacovigilance Update, 26 will attract even more interest in future. anniversary of the newsletter with September 2013, valproic acid and our approx. 2,700 subscribers. the safety of use during pregnancy Subscribe to Danish Pharmacovigilance in Danish Pharmacovigilance Update, Update. Over the past four years, the DHMA 25 April 2013, and a status of the study has dealt with many different topics mapping the consumption and the in the newsletter articles, ranging safety profile of the anticoagulant from updates of summaries of product Pradaxa® – a study carried out by characteristics and new potential the DHMA in collaboration with the signals to suspension of medicines. Thrombosis Centre in Aalborg in Danish Pharmacovigilance Update, In 2013, we have featured articles on 17 January 2013. topics such as the HPV vaccine Gardasil® against cervical cancer in

Danish Pharmacovigilance Update is published by: Danish Health and Medicines Authority http://www.sundhedsstyrelsen.dk/ English.aspx Editor-in-Chief: Henrik G. Jensen (HGJ) Editor: Nina Vucina Pedersen (NVP) ISSN 1904-2086

Danish Pharmacovigilance Update – Newsletter from the Danish Health and Medicines Authority