WHO Drug Information Vol. 27, No. 2, 2013

WHO Drug Information

Contents

Quality and Safety of Medicines Levothyroxine: licence suspension 111 WHO project for the surveillance Strontium ranelate: restricted use 112 and monitoring of SSFFC medical Tetrazepam-containing medicines: products 97 suspension 112 Dabigatran etexilate: updated Safety and Efficacy Issues contraindications 112 Azithromycin: potential risk of QT Idebenone: voluntary withdrawal 113 prolongation 101 Autologous chondrocyte implanta- Osteoporosis treatments: atypical tion approved for cartilage defects 113 femur fracture 102 Vismodegib approved for basal cell Ezogabine: retinal abnormalities carcinoma 114 and blue skin discoloration 103 Lenalidomide: approved for myelo- Incretin mimetics: risk of pancreatitis dysplastic syndromes 114 and pancreatic duct metaplasia 104 Nimodipine oral solution approved Incretin mimetics and GLP-1-based for subarachnoid haemorrhage 114 therapies: pancreatic risks 104 Golimumab approved for ulcerative Belatacept: acute graft rejection 105 colitis 115 Cinacalcet: fatal paediatric hypo- Radium dichloride approved for calcaemia 105 advanced prostate cancer 115 Cilostazol-containing medicines: Erlotinib and diagnostic test restricted use 106 approved for non-small cell Aqueous cream: skin irritation 106 lung cancer 115 Zolpidem products: lower doses Dabrafenib, trametinib and recommended 107 Valproate-related products: risks companion diagnostic test for during pregnancy 108 advanced skin cancer 116 Thalidomide: risk of second primary Cysteamine bitartrate approved for malignancies 108 rare genetic condition 116 Botulinum toxin type B: serious risks 108 Fluticasone furoate and vilanterol Magnesium sulphate during preg- approved for chronic obstructive nancy: teratogenic effects 109 pulmonary disease 117 Varenicline and buproprion: revision Oxycodone with abuse-deterrent to consumer information 109 properties approved 117 Imatinib approved for leukaemia 117 Regulatory Action and News First A1c test labelled for diagnosing Recommended influenza virus diabetes 118 vaccine composition: 2013–2014 Northern hemisphere season 110 The International Pharmacopoeia Counterfeit antimalarial medicines: International Meeting of World detection tool 110 Pharmacopoeias 119 Black triangle for medicines subject to additional monitoring 111 ... (continued)

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Contents (continued)

Recent Publications, Information ATC/DDD Classification and Events ATC/DDD Classification (Temporary) 130 Consortium to test kala-azar treat- ATC/DDD Classification (Final) 132 ments in East Africa 129 New guide to improve procurement International Nonproprietary performance 129 Names Proposed List No. 109 135

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96 WHO Drug Information Vol. 27, No. 2, 2013

Quality and Safety of Medicines

WHO project for the surveillance and monitoring of SSFFC medical products The existence of substandard/spurious/ hospitals, clinics, pharmacies and falsely labelled/falsified and counterfeit licensed entities within the regulated (SSFFC) medical products is not a supply chain — precisely the places new phenomenon, but is increasingly where patients should have the highest recognized by WHO Member States, level of confidence that the medicines regional groups and various international they receive are safe and effective. Every organizations as representing a incident damages confidence in health significant threat to human health. systems, medicines and healthcare professionals. The right to safe, efficacious, quality medicines which are affordable is a Despite this situation, there is no accurate fundamental human right. In some low global assessment of the scope, scale income countries access to healthcare and harm caused by the issue. Much facilities is limited; for those fortunate anecdotal information exists, but there enough to reach a facility they should be is a lack of clear, validated, reliable able to have trust and confidence in the evidence. Some excellent surveys have medicines they receive. Often, this is not been conducted in various parts of the case and with tragic consequences. the world. However, these reports are However, this situation — which was often short-term, restricted to limited once regarded as an issue solely geographic areas and may concentrate affecting low and middle income countries on specific therapeutic categories. They — now impacts all. The vast profits to are frequently used to extrapolate an be made through the high demand and estimate of the global threat which is less large turnover of medical products is a than sound and commonly challenged. powerful driver for those engaged in the Policy makers require reliable evidence manufacture, distribution and supply of upon which to base sound decisions SSFFC medical products. concerning the allocation of finite The rapid increase in connectivity to resources to tackle this damaging issue the Internet has also effectively opened in a proportionate way. up global markets to the distribution of SSFFC medical products. Whilst Surveillance and monitoring enabling access to medicines, it has also In 2010, WHO began to re-examine encouraged a culture of self-diagnosis existing methods and systems of and self-prescribing. Unregulated web collecting data concerning SSFFC sites have been seen in some parts of medical products. A rapid alert system the world as a key source of SSFFC had been developed in the Western products: an issue which is impossible to Pacific Region but was not being regularly regulate effectively and cannot be dealt used. During 2011, two consultative with by one country in isolation. meetings were held in Kiev, Ukraine and Kuala Lumpur, Malaysia. National Worryingly, incidents involving SSFFC regulatory authorities from the respective products are frequently reported from regions were asked to participate and

97 Quality and Safety of Medicines WHO Drug Information Vol. 27, No. 2, 2013 agree on methods to encourage the contacted by WHO within 72 hours. (In reporting of incidents. cases where adverse reactions are reported this is 24 hours). Building upon the good work started in the Western Pacific Region, a new SSFFC data base surveillance and monitoring system was On arrival at WHO, the details contained designed utilizing the submission of a on the Rapid Alert Form are automatically clear, concise and structured Rapid Alert downloaded and will populate the SSFFC Form to encourage a more systematic data base. The system will immediately method of reporting. The objective of identify duplicate reports. For example, the project is to significantly improve it will recognize if the specific batch/lot the quantity and quality of data enabling number of a medical product has been detailed analysis and validation of previously reported and will also match a incidents. range of other details. This allows cross matching of incidents and enables WHO Rapid Alert Form to put Member States in contact with Following further consultation, an elec- each other if dealing with linked incidents. tronic Rapid Alert Form was designed. At WHO, staff within the Quality and This template contains what is con- Safety of Medicines Team will also sidered to be the minimum amount of receive automatic notification of the information for WHO to conduct an initial arrival of a rapid alert. They will conduct risk assessment. Some of the data fields an immediate risk assessment with a are mandatory and failure to complete focus on the current threat to public these fields will prevent the document health and the need to communicate the from being forwarded to WHO. incident to any other countries which may be affected. Sharing of information is only The Rapid Alert Form contains a hidden conducted following consultation with the language recognition code. This enables originator of the report. the form to be completed in one language and automatically translated to English Review and analysis when downloaded into a data base WHO staff will make contact with the retained at WHO Headquarters. The originator of the Rapid Alert either by Rapid Alert Form is currently available telephone or e-mail and ask some in English and a French Version is being additional questions. They will start to tested. It is planned to make Spanish, populate the data base manually with Russian, Arabic and Mandarin versions any further information obtained from available. the originator. The data base contains over 250 fields which can be cross The form is provided as a template searched in any combination, permitting to trained focal points within national detailed analysis. The areas explored regulatory agencies. Once the mandatory in more detail contained within the fields are completed, the document can data base include: suspect product be saved and sent as an attachment via details, laboratory analysis, impact e-mail to [email protected]. Focal points on public health, risk communication, are encouraged to send any photographs, dissemination, method of distribution, laboratory reports or other relevant method of discovery, means and route documents as attachments. of import or export, details of who is responsible for any investigation, details Once sent, the originator will receive an of internet distribution, cost of medical automated message confirming receipt product, photographs of product and free and notifying them that they will be text comment and analysis areas.

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During this process, an analyst will be only after validation has been sought from looking for a range of characteristics in the originator that a final classification can order to make a final classification of the be carried out. case. Those characteristics include; Training workshop and pilot study • Unauthorized attempt to visually Following the consultation process, ten imitate the licensed, authorized or Member States agreed to participate approved product. in a pilot study. They are: Cambodia, • Attempt to mislead any person Croatia, Georgia, Indonesia, Kyrgyzstan, concerning product ingredients. Malaysia, Philippines, Russia, Ukraine, Viet Nam. • Incorrect, misleading or missing information as to the place of origin or In September 2012, the first 3-day manufacture. SSFFC training workshop was hosted in Manila by the Philippines Food and • Falsification of safety or security Drug Administration and held at the features. WHO Regional Office. The focal points from the ten pilot countries together with • Falsification of batch number, date of their immediate managers attended and manufacture or expiry dates. participated in five exercises involving • Falsification of any other aspect of recent SSFFC incidents. The USA packaging. and China sent observers from their respective regulatory agencies who • Falsification of license status, fully participated in the workshop. At the registration, authorisation or approval conclusion of each exercise, delegates information on packaging. were required to complete and submit the Rapid Alert Form to WHO. This training • Falsification of accompanying was immediately followed by the pilot documentation. study. • Was the product concealed or misdeclared during shipment? This took place between September 2012 and January 2013. Forty reports • Was the product stolen or diverted? involving 72 medical products were reported during this period concerning Final classification 30 active pharmaceutical ingredients. The Most cases should be closed within pilot study was designed to thoroughly 90 days and classified. The final test the system and identify scope for classification is designed to separate improvement. A number of refinements substandard medicines caused by were made to both the Rapid Alert Form, genuine manufacturing error from to improve ease of completion, and the incidents that demonstrate a clear data base, to facilitate better analysis. intention to deceive a patient, consumer, healthcare professional, or anybody else Challenges that the product is the genuine article. Incidents involving SSFFC medical products are hard to detect. It can be This final classification ensures that difficult to identify the harm caused by future trend analysis is based upon the the SSFFC product in a patient who comparison of similar incidents. Reports is already suffering from a disease. sometimes suggest that a product is However, WHO is working closely with falsified when in fact it is substandard due the WHO Collaborating Centre in Uppsala to an honest manufacturing error. It is to develop methods for mining data

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Case Study

In May 2013, WHO issued a drug alert relating to an antimalarial medicine circulating in Western and Central Africa which contained no active pharmaceutical ingredient. This branded product is a WHO prequalified medicine and was being distributed as part of the Global Fund AMFm programme. The genuine product is a reliable, trusted and effective medicine sought after in many sub-Saharan countries as an effective treatment for malaria. A German nongovernmental organization reported to WHO that samples they had recovered in Cameroon had failed mini-lab screening and had been sent to a WHO prequalified laboratory in Kenya for further analysis. Testing confirmed that the sample contained no active pharmaceutical ingredient. Further investigation with the genuine manufacturer of the medicine revealed that the same medicine bearing the same batch number had been seized in Angola as part of a World Customs Organization operation. A second batch of the same medicine had also been recovered during market surveillance in Benin and Nigeria. Recent information also suggested that at least two falsified batches containing no active pharmaceutical ingredient were currently circulating in Western and Central Africa. Initially, WHO issued a warning to all national regulatory authorities requesting increased vigilance. WHO was satisfied that a current and credible risk had been clearly identified which led to the publication of a WHO international drug alert to all Member States and publication on the WHO web site. relating to unusual clusters of reports of and to engage more Member States a lack of efficacy or adverse reactions in in use of the system. Closer links with patients which may be caused by sub- pharmacovigilance reporting will be potent SSFFC medical products. That developed. Further collaboration with work is on-going but pharmacovigilance WHO prequalified laboratories will reporting is seen as a potentially useful be encouraged. Extending the Rapid source of information. Alert Form to other stakeholders including procurement organizations, Next Steps nongovernment organizations and WHO is confident that a robust and other relevant stakeholders is under reliable system is now in place to receive consideration in an effort to achieve reports on incidents suspected to involve a more complete assessment of the SSFFC medical products. Three further situation. training workshops are planned for 2013 in Nigeria, Tanzania and Tunisia, which Conclusion will bring regulatory, pharmacovigilance Once sufficient reports are received and laboratory experts together. within the database, WHO will be in a Since the conclusion of the pilot study, position to report validated findings on a reports have continued to be submitted geographic or thematic basis. Reporting to WHO from a number of different should begin to identify supply chain sources. Over 130 products have now vulnerabilities and the finished medical been reported and are undergoing review products and active pharmaceutical and analysis. A number of cases have ingredients most at risk of falsification led to serious adverse reactions including and misrepresentation. This reporting will fatalities. influence recommendations for market surveillance, increased vigilance and WHO wishes to make the Rapid Alert the development of sound strategies to Form available in more languages minimize the risk from SSFFC products.

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Safety and Efficacy Issues

Azithromycin: potential risk currently 17 registered azithromycin- of QT prolongation containing products in Singapore, including the Zithromax® range of Singapore — Two recent research products, Zmax® and 11 other generic studies have strengthened the evidence products. regarding the potential risk of QT prolongation associated with the use Although closely related, macrolide drugs of azithromycin. In the light of this such as erythromycin and clarithromycin latest data, healthcare professionals are known to increase the risk of are advised to be aware of the risk of serious ventricular arrhythmias and are torsades de pointes and fatal arrhythmia associated with an increased risk of when considering azithromycin as a sudden cardiac death. Azithromycin has treatment option for patients who are previously been reported to be better at risk for cardiovascular events. These tolerated than other macrolides, and patient groups include (1): has minimal side effects (2). However, within the last year, two research studies • Patients with known prolongation of the have provided evidence on the risk QT interval, a history of torsades de of QT prolongation associated with pointes, congenital long QT syndrome, azithromycin. bradyarrhythmias, or uncompensated heart failure. One of the studies published in the New England Journal of Medicine (3) • Patients on drugs known to prolong the in May 2012 suggested a higher risk QT interval. of cardiovascular deaths and deaths • Patients with ongoing pro-arrhythmic from any cause in persons treated conditions such as uncorrected with a five-day course of azithromycin hypokalaemia or hypomagnesaemia, compared to persons treated with clinically significant bradycardia, and amoxicillin, ciprofloxacin, or no drug. patients receiving Class IA (quinidine, There were some limitations to this study, procainamide) or Class III (amiodarone, such as potential bias due to lack of sotalol) antiarrhythmic agents. randomization to the antibacterial drugs, outpatient setting investigation where it • Elderly patients and patients with is likely that few patients were treated cardiac disease who may be for severe or life-threatening infections, more susceptible to the effects of and the method of determination of arrhythmogenic drugs on the QT cardiovascular deaths through death interval. certificates instead of full medical records. Despite these, the study was noted to be Azithromycin is an azalide, a subclass methodologically sound and supportive of of macrolide antibiotics derived from the validity of the overall findings. erythromycin that is widely used both orally and intravenously for the treatment The estimated excess risk of cardio- of upper and lower respiratory tract vascular death compared with amoxicillin infections and other infections involving varied considerably with patient baseline susceptible organisms. There are cardiovascular risk, from roughly one in

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111,000 among healthier patients to Since 1996, the Health Sciences one in 4100 among high-risk patients. Authority (HSA) has received 181 The duration of the elevated risk of all- adverse drug reaction reports associated cause mortality and of cardiovascular with the use of azithromycin. death corresponded to the duration of azithromycin therapy. The increase Apart from azithromycin, other macro- in total deaths was determined to be lides such as erythromycin and clarithro- attributed to cardiovascular deaths and mycin or non-macrolides such as the not from other causes. The excess fluoroquinolones, are known to have risk of cardiovascular death, especially the potential for QT prolongation or of sudden death, was consistent with other significant side effects. Healthcare arrhythmias from drug-related QT professionals are advised to take into prolongation. consideration these factors when prescribing antibacterial treatment for The manufacturer of azithromycin also their patients. conducted a randomized, placebo- controlled parallel trial to assess the References effects of azithromycin on the QT interval in 116 healthy adults (1). These subjects 1. Zithromax® US package insert. Revised January 2013. received either chloroquine (1000 mg) alone or in combination with azithromycin 2. Russo V, Puzio G, Siniscalcji N. Azithro- (500 mg, 1000 mg, and 1500 mg once mycin-induced QT prolongation in elderly daily). Co-administration of azithromycin patient. Acta Biomed, 2006;77: 30–32; http:// increased the QTc* interval in a dose- www.actabiomedica.it/data/2006/1_ 2006/ and concentration-dependent manner. russo.pdf In comparison to chloroquine alone, the maximum mean (95% upper confidence 3. Ray WA, Murray KT, Hall K et al. bound) increases in QTcF** were 5ms Azithromycin and the Risk of Cardiovascular (10), 7ms (12) and 9ms (14) with the co- Death. NEJM 2012; 366:1881–90 administration of 500 mg, 1000 mg and 4. FDA Drug Safety Communication, Azithro- 1500 mg azithromycin, respectively. mycin (Zithromax® or Zmax®) and the risk of potentially fatal heart rhythms at http://www. The US FDA has updated the azithro- fda.gov/drugs/drugsafety/ucm341822.htm mycin package inserts to strengthen the warnings and precautions section 5. Health Sciences Authority, Safety Update, with information related to the risk of QT 29 April 2013 at http://www.hsa.gov.sg/publish/ interval prolongation and Torsades de hsaportal/en/health_products_regulation/ Pointes (4) Information regarding the safety_information/product_safety_alerts/ Safety_Alerts_2013/azithromycin_and_poten- results of the clinical QT study which tial.html showed that azithromycin can prolong the QTc interval has also been added. Osteoporosis treatments: atypical femur fracture *As the QT interval has an inverse relationship New Zealand — In November 2009, to heart rate, the measured QT interval is rou- tinely corrected by means of various formulae Medsafe highlighted an association to a value known as the QTc interval which is between alendronate and low-energy less dependent on the heart rate. femoral shaft fracture (1).

**the maximum mean difference in QT dura- Since then, similar cases have been tion corrected for heart rate by Fridericia’s published involving other bisphospho- Formula. nates as well as denosumab (Prolia®).

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Denosumab is a new treatment for References osteoporosis that is approved but not currently available in New Zealand. 1. Medsafe. Alendronate — risk of low-energy femoral shaft fracture. Prescriber Update 2009 Information on this risk is included 30(4): 25. in the data sheets for alendronate (Fosamax®), zolendronate (Zometa®) 2. Rizzoli R, Akesson K, Bouxsein M, et al. and pamidronate (Pamisol®). Subtrochanteric fractures after long-term treatment with bisphosphonates: a European To date there has been no confirmed Society on Clinical and Economic Aspects of association between strontium, teripara- Osteoporosis and Osteoarthritis, and Inter- tide, raloxifene or hormone replacement national Osteoporosis Foundation Working therapy and atypical fractures of the Group Report. Osteoporosis International femur. 2011 22(2): 373–390. Features associated with subtrochanteric 3. Warren C, Gilchrist N, Coates M, et al. and diaphyseal fractures include (2): Atypical subtrochanteric fractures, bisphos- phonates, blinded radiological review. ANZ • Minimal to no trauma. Journal of Surgery 2012 82: 908–912. • Transverse fracture line on radiography. 4. Prescriber Update 2013;34(1): 5–6 at http:// • Prodromal pain. www.medsafe.govt.nz/profs/PUArticles/Mar • Unilateral cortical beaking and bilateral 2013Osteoporosis.htm thickened diaphyseal cortices on radiography. Ezogabine: retinal abnormalities • Poor fracture healing. and blue skin discoloration The Centre for Adverse Reactions United States of America — The Food Monitoring (CARM) has received two and Drug Administration (FDA) has reports of fractures describing some reported that ezogabine (Potiga®) can of the features outlined above. In cause blue skin discoloration and eye both cases, the patient was taking abnormalities characterized by pigment alendronate. changes in the retina. The FDA does Atypical subtrochanteric fractures are not currently know if these changes are rare, less than 0.1% of total fractures in a reversible. All patients taking ezogabine New Zealand study (3). For a population should have a baseline eye exam, of 10,000 patients at high risk of fracture, followed by periodic eye exams. bisphosphonate treatment might be expected to prevent 108 hip fractures Pigment changes in the retina have the (and around 750 other fractures) per potential to cause serious eye disease year and result in three subtrochanteric with loss of vision. It is not yet known fractures (2). Therefore, the benefit whether the retinal pigment changes risk ratio for bisphosphonate treatment caused by ezogabine lead to visual remains favourable. impairment, although several patients have been reported to have impaired In patients with atypical femoral fractures, visual acuity. bisphosphonate treatment should be considered as a possible cause. The skin discoloration in the reported Interruption of bisphosphonate therapy cases appeared as blue pigmentation, may be necessary for fracture healing. predominantly on or around the lips or Re-treatment should be considered if in the nail beds of the fingers or toes, bone density again begins to fall and after but more widespread involvement of the a discussion of the benefits and risks with face and legs has also been reported. the patient. Scleral and conjunctival discoloration,

103 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 2, 2013 on the white of the eye and inside with diet and exercise to lower blood eyelids, has been observed as well. Skin sugar in adults with type 2 diabetes. discoloration generally occurred after four years of treatment with ezogabine, The FDA has not reached any new but has appeared sooner in some conclusions about safety risks with patients. Retinal abnormalities have also incretin mimetic drugs but intends to been observed in the absence of skin obtain and evaluate this new information discoloration. following participation in the National Institute of Diabetes and Digestive and In light of this new safety information, Kidney Diseases (NIDDK) and National all patients taking ezogabine or about to Cancer Institute’s (NCI) Workshop on start, should have an eye exam followed Pancreatitis-Diabetes-Pancreatic Cancer by periodic eye exams thereafter. held in June 2013 to gather and share Ezogabine should be discontinued if additional information. ophthalmic changes are observed unless Reference: FDA Drug Safety Communication, no other treatment options are available. 14 March 2013 at http://www.fda.gov/Safety/ If a patient develops skin discoloration, MedWatch/SafetyInformation/SafetyAlertsfo- serious consideration should be given to rHumanMedicalProducts/ucm343805.htm changing to an alternate medication. Reference: FDA Drug Safety Communication, Incretin mimetics and GLP-1-based 26 April 2013 at http://www.fda.gov/Drugs/ therapies: pancreatic risks DrugSafety/ucm349538.htm European Union — The European Incretin mimetics: risk of Medicines Agency (EMA) is investigating findings by a group of independent pancreatitis and pancreatic academic researchers that suggest duct metaplasia an increased risk of pancreatitis United States of America — The and pancreatic duct metaplasia in Food and Drug Administration (FDA) is patients with type 2 diabetes treated evaluating unpublished new findings that with glucagon-like peptide 1 (GLP-1) suggest an increased risk of pancreatitis based therapies (GLP–1 agonists and and pancreatic duct metaplasia in dipeptidylpeptidase-4 (DPP–4) inhibitors). patients with type 2 diabetes treated The findings are based on examination with incretin mimetics. These findings of a small number of pancreatic tissue were based on examination of a small samples obtained from organ donors number of pancreatic tissue specimens with and without diabetes mellitus, who taken from patients after they died from died due to causes other than diabetes. unspecified causes. The Agency’s Committee for Medicinal Products for Human Use (CHMP) and Drugs in the incretin mimetic class the Pharmacovigilance Risk Assessment include exenatide (Byetta®, Bydureon®), Committee (PRAC) are currently liraglutide (Victoza®), sitagliptin investigating the information provided by (Januvia®, Janumet®, Janumet XR®, the researchers to determine the need for Juvisync®), saxagliptin (Onglyza®, possible further regulatory action. Kombiglyze XR®), alogliptin (Nesina®, Kazano®, Oseni®), and linagliptin The Agency has not reached any (Tradjenta®, Jentadueto®). These drugs conclusions on this investigation. work by mimicking the incretin hormones There is currently no change to the that the body usually produces naturally recommendations on the use of these to stimulate the release of insulin in medicines and no need for patients to response to a meal. They are used along stop taking their medicines.

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There are also efforts underway to Corticosteroid tapering should be collect safety data on diabetes medicines implemented cautiously, particularly from independent pharmacovigilance in patients with 4–6 human leukocyte centres across the European Union. antigen (HLA) mismatches. The The SAFEGUARD study, a study that is product information will be updated to funded by the European Commission and include a warning on rapid tapering carried out within the European Network of corticosteroids in patients with high of Centres for Pharmacoepidemiology immunologic risk and provide information and Pharmacovigilance (ENCePP), is on the corticosteroid doses used and the investigating, among others, evidence populations included in the clinical studies for drug-induced pancreatitis for GLP–1- supporting the approval of Nulojix®. based agents that were authorized before 2011, when the study started. Nulojix® in conjunction with basiliximab induction, mycophenolate mofetil and GLP–1-based therapies are also known corticosteroid taper to 5 mg/day by week as incretin mimetics. In the EU they 6 post-transplant, has been associated include exenatide (Byetta®, Bydureon®), with an increased rate of acute rejection, liraglutide (Victoza®), lixisenatide particularly Grade III rejection in the (Lyxumia®), sitagliptin (Efficib®, postmarketing setting. These Grade III Januvia®, Janumet®, Ristaben®, rejections occurred in patients with 4 to Ristfor®, Tesavel®, Velmetia®, Xelevia®), 6 HLA mismatches. This corticosteroid saxagliptin (Komboglyze®, Onglyza®), taper was more rapid than that used linagliptin (Jentadueto®, Trajenta®) in the clinical studies supporting the and vildagliptin (Eucreas®, Galvus®, approval of Nulojix®. Icandra®, Jalra®, Xiliarx®, Zomarist®). Reference: Healthcare Products Regulatory Agency (MHRA). Healthcare Professional Reference: EMA Press Release, EMA/ Communication March 2013 at http://www. 178662/2013. 26 March 2013. http://www. medicines.org.uk/EMC/medicine ema.europa.eu/ema/index.jsp?curl=pages/ news_and_events/news/2013 Cinacalcet: fatal paediatric Belatacept: acute graft rejection hypocalcaemia United Kingdom — In agreement with United Kingdom — A fatal case with the European Medicines Agency (EMA) severe hypocalcaemia has occurred and the Medicines and Healthcare in a paediatric investigational study of Products Regulatory Agency (MHRA), the cinacalcet (Mimpara®). The manufacurer manufacturer of belatacept (Nulojix®) has has suspended dosing, screening and informed healthcare professionals that enrolment in all paediatric cinacalcet an increased rate of acute graft rejection investigational studies and is investigating has been reported postmarket when this case to determine if any additional corticosteroids have been rapidly tapered action is necessary. in patients at high immunologic risk for Cinacalcet is approved only in adults. acute rejection. The product information warns of the risk of hypocalcaemia associated with Nulojix® in combination with cortico- cinacalcet. Therefore, patients should be steroids and a mycophenolic acid is carefully monitored for the occurrence of indicated for prophylaxis of graft rejection hypocalcaemia. in adults receiving a renal transplant. It is recommended to add an interleukin (IL)-2 Cinacalcet is indicated for the treatment receptor antagonist for induction therapy of secondary hyperparathyroidism (HPT) to this belatacept-based regimen. in patients with end-stage renal disease

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(ESRD) on maintenance dialysis therapy. CHMP to carry out a review of these Cinacalcet may be used as part of a medicines following a number of reports therapeutic regimen including phosphate of serious suspected side effects, in binders and/or vitamin D sterols, as particular affecting the heart, as well as appropriate. cases of serious bleeding. Cinacalcet is also indicated for the References reduction of hypercalcaemia in patients with parathyroid carcinoma, or primary 1. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral HPT for whom parathyroidectomy artery disease: the CASTLE study (Cilostazol: would be indicated on the basis of A Study in Long-term Effects). J Vasc Surg. serum calcium levels (as defined by 2008;47:330–336. relevant treatment guidelines) but in whom parathyroidectomy is not clinically 2. EMA Press Release. EMA/ 98571/2013. appropriate or is contraindicated. 22 March 2013 at http://www.ema.europa. eu/ema/index.jsp?curl=pages/news_and_ Reference: Healthcare Products Regulatory events/news/2013/03/news_detail_001746. Agency (MHRA). Healthcare Professional jsp&mid=WC0b01ac058004d5c1 Communication 20 March 2013 at http://www. medicines.org.uk/EMC/medicine Aqueous cream: skin irritation

Cilostazol-containing medicines: United Kingdom — Aqueous cream is restricted use a widely used product topically applied as an emollient for the symptomatic relief European Union — The Committee of dry skin conditions such as atopic on Medicinal Products for Human Use eczema, and as a soap-substitute for skin (CHMP) has recommended that the use washing. of cilostazol-containing medicines in the treatment of intermittent claudication Although aqueous cream is useful as should be restricted. Cilostazol-containing a leave-on emollient in a substantial medicines are available in the EU under proportion of patients with eczema, it is the names Pletal® and Ekistol®. known that in some patients, especially in children, it can cause skin reactions, such The recommendations follow a review of as stinging, burning, itching and redness. current evidence which indicates that the modest benefits of these medicines are In light of new information from the only greater than their risks in a limited published literature all data on the subgroup of patients. benefits and risks of aqueous cream, particularly when used in children with The Committee recommended that eczema, have been recently reviewed cilostazol should only be used in patients in the UK (1). An audit of 100 children whose symptoms have not improved attending a paediatric dermatology clinic despite prior lifestyle changes. In reported that aqueous cream emollient addition, cilostazol-containing medicines was associated with an immediate skin should not be used in patients who have reaction (stinging, burning, itching, and suffered severe tachyarrhythmia or redness) within 20 minutes in 56% of recent unstable angina, heart attack or exposures, compared with 18% with bypass surgery, or who take two or more other emollients used (2). Furthermore, antiplatelet or anticoagulant medicines several studies reported alterations in such as aspirin and clopidogrel. skin physiology (thinning of the outermost layer of the skin and increased skin water The Spanish Agency for Medicines and loss) following application of aqueous Health Products (AEMPS) asked the cream as an emollient in adults, both with

106 WHO Drug Information Vol. 27, No. 2, 2013 Safety and Efficacy Issues and without eczema (3, 4). A summary of 6. Guidelines from the National Eczema all the evidence reviewed is available in Society at http://www.eczema.org. the public assessment report (5). 7. Medicines and Healthcare products Regu- The causative agent may be sodium latory Agency (MHRA). Drug safety advice, lauryl sulfate (SLS), contained in Volume 6, Issue 8, March 2013 at http://www. emulsifying wax which is one of the mhra.gov.uk/Safetyinformation ingredients of aqueous cream. SLS functions as a stabilizer and cleansing Zolpidem products: lower agent and is a known skin irritant. doses recommended However, aqueous cream products often contain other ingredients such as United States of America — The Food chlorocrescol, cetostearyl alcohol and and Drug Administration (FDA) has parabens, which may also cause or approved label changes specifying new contribute to adverse skin reactions. dosing recommendations for zolpidem products (Ambien®, Ambien CR®, and Despite the potential irritant effects Edluar®) because of the known risk of reported in the literature, in clinical next-morning impairment. practice aqueous cream used both as an emollient and a wash-off soap FDA has also warned that patients who substitute has been useful in a substantial take the sleep medication zolpidem proportion of patients with atopic eczema. extended-release (Ambien CR®) ― either 6.25 mg or 12.5 mg ― should not drive On the basis of the review, aqueous or engage in other activities that require cream labelling and the information leaflet mental alertness the day after taking the will be updated with a warning on the drug because zolpidem levels can remain potential of local skin reactions, and SLS high the next day. will be listed as an ingredient (6–7). Also included in the updated label are References the dosing recommendations previously published on 10 January 2013 in FDA 1. Medicines and Healthcare Products Regu- latory Agency (MHRA). Public Assessment Drug Safety Communication. The Report at http://www.mhra.gov.uk/Safetyinfor- recommended initial dose of certain mation/Safetywarningsalertsandrecalls/ immediate-release zolpidem products UKsafetyPublicAssessmentReports/ (Ambien and Edluar®) is 5 mg for women CON251956/7. and either 5 mg or 10 mg for men. The recommended initial dose of zolpidem 2. Cork MJ et al (2003). An audit of adverse extended-release (Ambien CR®) is drug reactions to aqueous cream in children 6.25 mg for women and either 6.25 or with atopic eczema. Pharm J 271(7277): 12.5 mg for men. If the lower doses (5 747–745. mg for immediate-release, 6.25 mg for 3. Tsang M and Guy RH (2010). Effect of extended-release) are not effective, aqueous cream BP on human stratum cor- the dose can be increased to 10 mg for neum in vivo. Br J Dermatol 163(5): 954–958. immediate-release products and 12.5 mg for zolpidem extended-release. However, 4. Danby SG et al (2011). The effect of use of the higher dose can increase the aqueous cream BP on the skin barrier in risk of next-day impairment of driving and volunteers with a previous history of atopic other activities that require full alertness. dermatitis. Br J Dermatol 165 (2):329–334. Reference: FDA Drug Safety Commu- 5. NICE Guideline. Clinical Guideline: Atopic nication, 14 May 2013 at http://www. eczema in children (CG57) at http://guidance. fda.gov/Drugs/DrugSafety/ucm352085. nice.org.uk/CG57. htm?source=govdelivery

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Valproate-related products: myeloma, in combination with melphalan risks during pregnancy and prednisone.

United States of America — The Second primary malignancies, in Food and Drug Administration (FDA) particular, acute myeloid leukemia (AML) has alerted healthcare providers and and myelodysplastic syndrome (MDS), patients that medications including and have been observed in an ongoing related to valproate sodium can cause clinical trial in patients with previously decreased IQ scores in children whose untreated multiple myeloma receiving the mothers took the medication during combination melphalan, prednisone and pregnancy. Therefore, these drugs Thalomid® (MPT). AML and MDS have are being contraindicated for migraine been rarely reported in the post-market headaches. Valproate products include setting. valproate sodium (Depacon®), divalproex sodium (Depakote®, Depakote CP®, Physicians should carefully evaluate and Depakote ER®), valproic acid patients before and during treatment (Depakene® and Stavzor®), and their using standard cancer screening generics. for occurrence of second primary malignancies. Valproate products have several FDA- approved uses including: prevention Reference: Health Canada Safety of migraine, treatment of epilepsy and Communication, 16 May 2013 at http:// treatment of manic episodes associated healthycanadians.gc.ca/recall-alert-rappel- avis/hc-sc/2013/29245a-eng.php with bipolar disorder. Women who can become pregnant should not use valproate unless it is essential to Botulinum toxin type B: managing their medical condition. serious risks United Kingdom — Botulinum toxin type Medicines that contain valproate already B (Neurobloc®) is indicated only for the have a boxed warning for foetal risk, treatment of cervical dystonia in adults. including birth defects. The recently The Medicines and Healthcare Products published Neurodevelopmental Effects of Regulatory Agency (MHRA) recommends Antiepileptic Drugs (NEAD) study found that prescribers adhere to the licensed further evidence of the IQ risk. indication as its safety outside these Reference: FDA News Release, 6 May 2013 circumstances has not been established. at http://www.fda.gov/NewsEvents/Newsroom/ Cases of the known rare risk of toxin PressAnnouncements/ucm350866.htm spread have been reported with all botulinum toxin products. Importantly, the Thalidomide: risk of second cases with botulinum toxin type B were primary malignancies mostly reported with its off-label use.

Canada — Health Canada has informed All patients receiving any product healthcare professionals of important new containing botulinum toxin should be safety information which has been added warned of the signs and symptoms of to the Product Monograph for thalidomide toxin spread, such as muscle weakness capsules (Thalomid®). and breathing difficulties, and be advised to seek medical attention immediately Thalidomide is an immunomodulatory if they experience breathing difficulties, agent indicated for the treatment of choking, or any new or worsening patients who are 65 years of age or swallowing difficulties, as such side older with previously untreated multiple effects may be life-threatening.

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Reference: Medicines and Healthcare Varenicline and buproprion: Products Regulatory Agency (MHRA). Drug revision to consumer information Safety Advice, Volume 6, Issue 8, March 2013 at http://www.mhra.gov.uk/Safetyinformation/ Canada — Health Canada has informed healthcare professionals that new Magnesium sulphate during information for varenicline tartrate pregnancy: teratogenic effects (Champix®) and bupropion hydrochloride (Zyban®) has been added to the product United States of America — The Food information to indicate that nicotine and Drug Administration (FDA) has replacement therapy (patches, gum, advised healthcare professionals against lozenges, etc.) should be considered using magnesium sulfate injection for before taking non-nicotine medicines. more than 5–7 days to stop pre-term labor in pregnant women. This use of This revision was based on available the drug is off-label. Administration of information about the treatments magnesium sulfate injection to pregnant used to help people stop smoking. women longer than 5–7 days may lead Nicotine replacement therapy should to low calcium levels and bone problems be considered before non-nicotine in the foetus, including osteopenia and replacement. fractures. Reference: Health Canada Safety Magnesium sulfate is approved to prevent Communication, 30 May 2013 at http://www. seizures in pre-eclampsia and for control http://healthycanadians.gc.ca/recall-alert- of seizures in eclampsia. rappel-avis/hc-sc/2013/33623a-eng.php

Reference: FDA Safety Communication, 30 May 2013 at http://www.fda.gov/Drugs/ DrugSafety/ucm353333.htm

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented pre- viously. 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”. All signals must be vaidated before any regulatory decision can be made.

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Regulatory Action and News

Recommended influenza virus Counterfeit antimalarial vaccine composition: 2013–2014 medicines: detection tool Northern hemisphere season United States of America — The Food Wold Health Organization — It is and Drug Administration (FDA) has recommended that vaccines for use in the announced a public-private partnership 2013–2014 influenza season (Northern to identify counterfeit or substandard hemisphere Winter) contain the following: antimalarial medicines, including falsified products, with the deployment of the • An A/California/7/2009 (H1N1)pdm09- FDA-developed Counterfeit Detection like virus (A/Christchurch/16/2010 is an Device, called CD-3. A/California/7/2009-like virus). Globally, malaria kills more than • An A(H3N2) virus antigenically like 660,000 people annually, mostly the cell-propagated prototype virus children. The threat of drug resistance, A/Victoria/361/2011 (A/Texas/50/2012 limited availability of medication and is an A(H3N2) virus antigenically increased presence of counterfeit or like the cell-propagated prototype substandard antimalarial medicines virus A/Victoria/361/2011). It is pose significant challenges to treating recommended that A/Texas/50/2012 this disease. Compromised antimalarials is used as the A(H3N2) vaccine often have too little or no active ingre- component because of antigenic dients, preventing adequate and timely changes in earlier A/Victoria/361/2011- treatment. Antimalarial medicines like vaccine viruses (such as IVR-165) made with reduced dosages of active resulting from adaptation to propagation ingredients will not cure patients, and in eggs. they can lead to resistant strains of the parasite, making it tougher to treat, even • A B/Massachusetts/2/2012-like virus. with authentic medicines. • It is recommended that quadrivalent vaccines containing two influenza The FDA has established a partnership B viruses contain the above three with the Skoll Global Threats Fund, the viruses and a B/Brisbane/60/2008- U.S. Pharmacopeia (USP), the National like virus (B/Brisbane/33/2008 is a Institutes of Health (NIH), the Centers for B/Brisbane/60/2008-like virus). Disease Control and Prevention (CDC), and the multi-agency President’s Malaria As in previous years, national or regional Initiative (PMI), led by the U.S. Agency for International Development (USAID). authorities approve the composition and formulation of vaccines used in The partnership will focus on testing and each country. National public health optimizing the use of the handheld CD-3 authorities are responsible for making to identify counterfeit or substandard recommendations regarding use of the antimalarial medicines, including falsified vaccine. products, in Africa and parts of South- Reference: Weekly Epidemiological Record, east Asia where the rates of malaria 8 March 2013, vol. 88, 10 (pp. 101–116) at infection are high and where counterfeit http://www.who.int/wer antimalarial medicines are prevalent.

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The effectiveness of the tool in detecting • Medicines for which the marketing- counterfeit or substandard versions authorization holder is required to carry of two common antimalarial therapies out a post-authorization safety study will be tested in Ghana in 2013 and (PASS). 2014. Making detection technology more accessible to low and middle Other medicines can also be placed income countries would be invaluable under additional monitoring, based on in controlling the trade in counterfeit, a recommendation from the European falsified, or substandard medicines. Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). Reference: FDA News Release, April 2013 A medicine can be included on this list at http://www.fda.gov/NewsEvents/Newsroom/ when it is approved for the first time or PressAnnouncements at any time during its lifecycle. It remains under additional monitoring for five years Black triangle for medicines or until the PRAC decides to remove it subject to additional monitoring from the list usually because studies have further established the safety profile of European Union —The European the product concerned. The complete Medicines Agency (EMA) has published additional-monitoring list will be reviewed an initial list of medicines that are subject every month by the PRAC and published to additional monitoring. This represents on the EMA web site, where additional a deliverable of the new European information on monitoring can also be pharmacovigilance legislation. These found in all EU languages. medicines will have to display an inverted back triangle in their package leaflet and The inverted black triangle will start in the summary of product characteristics appearing in the package leaflet and (SmPC), together with a short sentence SmPC of the medicines concerned from explaining what the triangle means. the autumn of 2013.

All medicines on the European Union Reference: EMA Press Release, 25 April market are carefully monitored. If a 2013 at http://www.ema.europa.eu/ema/ index.jsp?curl=pages/news_and_events/ medicine is labelled with the inverted news/2013/04/news black triangle, it does not mean that it is unsafe; the purpose of the symbol is to actively encourage healthcare Levothyroxine: licence suspension professionals and patients to report any United Kingdom — The Medicines and suspected adverse reactions observed Healthcare Products Regulatory Agency with the medicine, either because the (MHRA) has suspended the licence for medicine is new to the market or because levothyroxine 100 microgram tablets there is a limitation to the data available for patients with hypothyroidism. This on its safety. Medicines subject to follows manufacturing difficulties and additional monitoring are: concerns that the product might not be • Medicines authorized after 1 January interchangeable with other available 2011 that contain a new active levothyroxine 100 mcg tablets. substance. The decision to suspend follows a review • Biological medicines for which there is by the Commission on Human Medicines limited post-marketing experience. (CHM), the MHRA’s independent advisory body, of manufacturing issues • Medicines with a conditional approval and sporadic reports of loss of control of or approved under exceptional hypothyroidism when switching between circumstances. products.

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Pregnant women, those with heart Decentralized Procedures: Human disease and those under treatment (CMDh) has endorsed the Pharmaco- with levothyroxine following treatment vigilance Risk Assessment Committee for thyroid cancer may be particularly (PRAC) recommendation to suspend the susceptible to changes in thyroid marketing authorizations of tetrazepam- stimulating hormone and may require containing medicines across the close monitoring by their doctor. European Union (EU). The CMDh, a body representing Member States, is Reference: Medicines and Healthcare responsible for ensuring harmonized Products Regulatory Agency. MHRA Press safety standards for medicines authorized Release, 16 February 2012 at http://www. mhra.gov.uk/NewsCentre/Pressreleases/ via national marketing authorization CON143688 procedures. Tetrazepam, a medicine of the benzo- Strontium ranelate: restricted use diazepine class, is used in several European Union — The Committee Member States to treat painful for Medicinal Products for Human Use contractures and spasticity. The review (CHMP) has recommended a restriction of tetrazepam was triggered by the in the use of the osteoporosis medicine French National Agency for the Safety of strontium ranelate (Protelos/Osseor®), Medicine and Health Products (ANSM), following an assessment of data showing following reports of serious skin reactions an increased risk of serious heart with this medicine in France. problems. The CHMP recommended Having assessed all available data on that Protelos/Osseor® should only be the risk of skin reactions, the PRAC used to treat severe osteoporosis in concluded that tetrazepam is associated postmenopausal women at high risk of with a low but increased risk of serious fracture and severe osteoporosis in men skin reactions (including Stevens- at increased risk of fracture. Additional Johnson syndrome, toxic epidermal measures, including restrictions in necrolysis and DRESS syndrome) patients with heart or circulatory compared with other benzodiazepines. problems, were also recommended The Committee also noted that the to minimize the heart risks of these available data on the effectiveness of medicines. Treatment should be stopped tetrazepam were not sufficiently robust if the patient develops ischaemic heart to support its use for the authorized disease, peripheral arterial disease indications. or cerebrovascular disease or if hypertension becomes uncontrolled. Reference: EMA Press Release, 29 April 2013 at http://www.ema.europa.eu/ema/ The CHMP recommendation is based on index.jsp?curl=pages/news_and_events/ the advice of the Pharmacovigilance Risk news/2013/04/news_detail_001777. Assessment Committee (PRAC). jsp&mid=WC0b01ac058004d5c1 Reference: EMA Press Release, 26 April 2013 at http://www.ema.europa.eu/ema/ Dabigatran etexilate: updated index.jsp?curl=pages/news_and_events/ contraindications news/2013/04/news European Union — On 25 April 2013, Tetrazepam-containing medicines: the Committee for Medicinal Products for Human Use (CHMP) adopted a positive suspension opinion recommending a change to the European Union — The Coordination contraindication for dabigatran etexilate Group for Mutual Recognition and (Pradaxa®).

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Contraindications for Pradaxa® are now: Idebenone: voluntary withdrawal

• Hypersensitivity to the active substance Canada — Health Canada has or to any of the excipients. informed healthcare professionals of the manufacturer’s decision to voluntarily • Severe renal impairment (CrCL < 30 withdraw idebenone (Catena®) from the mL/min). Canadian market, as of 30 April 2013. • Active clinically-significant bleeding. The withdrawal is based on the negative outcome of additional confirmatory • Lesion or condition, if considered efficacy studies required by Health a significant risk factor for major Canada and is not the result of a specific bleeding such as current or recent safety concern. Prescribers are advised gastrointestinal ulceration, presence to discuss alternative treatment options of malignant neoplasms at high with their patients. risk of bleeding, recent brain or spinal injury, recent brain, spinal or Idebenone was authorized with conditions ophthalmic surgery, recent intracranial in Canada in July 2008 on the basis of haemorrhage, known or suspected promising evidence of clinical safety and oesophageal varices, arteriovenous efficacy in the symptomatic management malformations, vascular aneurysms of patients with Friedreich Ataxia. One of or major intraspinal or intracerebral the conditions of authorization was to vascular abnormalities. provide confirmatory evidence of efficacy in further clinical studies. However, the • Concomitant treatment with any other additional studies completed to date anticoagulants e.g. unfractionated failed to meet their primary efficacy heparin (UFH), low molecular weight endpoint. The manufacturer will not recall heparins (enoxaparin, dalteparin etc), Catena® currently prescribed. heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, Reference: Health Canada. Medeffect Adviso- rivaroxaban, apixaban etc) except ries, warnings and recalls, 27 February 2013 under the circumstances of switching at http://www.hcsc.gc.ca. therapy to or from Pradaxa® (or when UFH is given at doses necessary to Autologous chondrocyte implanta- maintain an open central venous or tion approved for cartilage defects arterial catheter. European Union — The European • Hepatic impairment or liver disease Medicines Agency (EMA) Committee expected to have any impact on for Medicinal Products for Human Use survival. (CHMP) has recommended marketing • Concomitant treatment with systemic authorization for Maci® (matrix-induced ketoconazole, cyclosporine, itra- autologous chondrocyte implantation), conazole, tacrolimus and dronedarone. an advanced-therapy medicinal product (ATMP), for the repair of symptomatic, • Prosthetic heart valves requiring full-thickness cartilage defects of the knee anticoagulant treatment. in skeletally mature adult patients.

Reference: Committee for Medicinal Products Cartilage has a poor ability to repair for Human Use (CHMP). Summary of opinion itself when injured. Injuries to the (post authorization) for Pradaxa/dabigatran smooth cartilage surface of the knee etexilate. EMA/CHMP/261823/2013, 25 April joint increase rubbing and friction in 2013 at http://www.ema.europa.eu the knee and predispose the knee to

113 Regulatory Action and News WHO Drug Information Vol. 27, No. 2, 2013 further cartilage wear and erosion, which differentiation of cells. The benefits with can eventually lead to osteoarthritis if Erivedge® are its ability to reduce lesion untreated. size or sum of the longest diameter of lesions more than 30% or to provide A number of surgical procedures aiming complete resolution of ulceration in all to repair cartilage have been developed target lesions in 48% of the patients with to treat patients with articular cartilage locally advanced BCC and in 33% of the defect of the knee. One of them is patients with metastatic BCC. The most autologous chondrocyte implantation common side effects are muscle spasms, (ACI), a therapy based on tissue alopecia, dysgeusia, weight decreased, engineering, which was first described in fatigue and nausea. There is a high risk 1994. It uses chondrocytes, or cartilage that vismodegib can cause embryo-foetal cells, which are derived from the patient’s death or severe birth defects. own cartilage, grown outside the patient’s Reference: EMA Press Release, EMA/ body and then transplanted into the CHMP/263262/2013. 25 April 2013 at patient’s lesions after several weeks. http://www.ema.europa.eu/ema/index. The benefit of ACI over other restoration jsp?curl=pages/news_and_events/ techniques is that larger lesions can be news/2013/04/news treated. Lenalidomide: approved for Maci® is a third-generation ACI product myelodysplastic syndromes which uses a scaffold formed of por- cine collagen on which autologous European Union — The Committee chondrocytes are seeded. At implantation, for Medicinal Products for Human Use the scaffold is trimmed to the size and (CHMP) has recommended a variation to shape of the cartilage defect. The cells/ the terms of the marketing authorization collagen structure is held in place in the for lenalidomide (Revlimid®). lesion with fibrin glue. The CHMP adopted a new indication for Reference: EMA Press Release, 26 April 2013 at http://www.ema.europa.eu/ema/ myelodysplastic syndromes. Revlimid® index.jsp?curl=pages/news_and_events/ is now also indicated for the treatment news/2013/04/news of patients with transfusion-dependent anaemia due to low- or intermediate- Vismodegib approved for 1-risk myelodysplastic syndromes associated with an isolated deletion basal cell carcinoma 5q cytogenetic abnormality when other European Union — The Committee therapeutic options are insufficient or for Medicinal Products for Human Use inadequate. (CHMP) has recommended the granting of a conditional marketing authorization Reference: EMA Press Release, EMA/ for vismodegib (Erivedge®) 150 mg, CHMP/244652/2013. 25 April 2013 at hard capsule, intended for the treatment http://www.ema.europa.eu/ema/index. jsp?curl=pages/news_and_events/ of adult patients with symptomatic news/2013/04/news metastatic basal cell carcinoma (BCC) or locally advanced basal cell carcinoma inappropriate for surgery or radiotherapy. Nimodipine oral solution approved for subarachnoid haemorrhage Vismodegib, an antineoplastic agent, United States of America — The Food is an orally available small-molecule and Drug Administration (FDA) has which acts by blocking specific genes approved Nymalize®, a new nimodipine involved in proliferation, survival, and oral solution to treat patients with

114 WHO Drug Information Vol. 27, No. 2, 2013 Regulatory Action and News symptoms resulting from subarachnoid nervous system disorders and allergic haemorrhage. Nimodipine was previously reactions. available only as a liquid-filled gel capsule. Reference: FDA News Release, 15 May 2013 at http://www.fda.gov/NewsEvents/Newsroom/ The FDA has received reports of serious PressAnnouncements and sometimes fatal consequences from intravenous (IV) injection of the Radium dichloride approved for liquid contents of oral nimodipine advanced prostate cancer capsules. IV administration of nimodipine meant for oral use can result in death, United States of America — The cardiac arrest, severe decreases in Food and Drug Administration (FDA) blood pressure and other heart-related has approved radium 223Ra dichloride complications. (Xofigo®) to treat men with symptomatic metastatic castration-resistant prostate The approval of Nymalize® is based cancer that has spread to bones but not on clinical studies evaluating the use of to other organs. It is intended for men nimodipine oral capsules in patients with whose cancer has spread after receiving subarachnoid haemorrhage. The most medical or surgical therapy to lower common adverse event observed in the testosterone. studies was decreased blood pressure. The most common side effects reported Reference: FDA News Release, 14 May 2013 during clinical trials in men receiving at http://www.fda.gov/NewsEvents/Newsroom/ Xofigo® were nausea, diarrhoea, PressAnnouncements vomiting and swelling of the leg, ankle or foot. The most common abnormalities Golimumab approved detected during blood testing included for ulcerative colitis anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia. United States of America — The Food and Drug Administration (FDA) has Reference: FDA News Release, 15 May 2013 approved a new use for golimumab at http://www.fda.gov/NewsEvents/Newsroom/ (Simponi®) injection to treat adults with PressAnnouncements moderate to severe ulcerative colitis. Golimumab works by blocking tumour Erlotinib and diagnostic test necrosis factor (TNF). Previously approved for non-small cell approved to treat rheumatoid arthritis, lung cancer psoriatic arthritis and ankylosing spondylitis, Simponi® is now approved United States of America — The Food to treat adults with moderate to severe and Drug Administration (FDA) has ulcerative colitis that is rrefractory to approved the cobas EGFR Mutation Test, prior treatment or requires continuous a companion diagnostic for the cancer corticosteroid therapy. drug erlotinib (Tarceva®). This is the first FDA-approved companion diagnostic that The most common side effects in detects epidermal growth factor receptor patients treated with Simponi® are (EGFR) gene mutations, which are upper respiratory infection and redness present in approximately 10 percent of at the site of injection. Patients treated non-small cell lung cancers (NSCLC). with Simponi® are at increased risk of developing serious infections, invasive The test is being approved with an fungal infections, reactivation of Hepatitis expanded use for erlotinib as a first-line B infection, lymphoma, heart failure, treatment for patients with NSCLC that

115 Regulatory Action and News WHO Drug Information Vol. 27, No. 2, 2013 has metastasized and who have certain common side effects reported in patients mutations in the EGFR gene. receiving Tafinlar® included hyperkerato- sis, headache, fever, joint pain, non-can- The FDA approved Tarceva® on 16 cerous skin tumors, hair loss and hand- April 2010 for maintenance treatment foot syndrome. of patients with locally advanced or metastatic NSCLC whose disease has The most serious side effects reported not progressed after four cycles of in patients receiving Mekinist® included platinum-based first-line chemotherapy. heart failure, lung inflammation, skin infections and loss of vision. Common Reference: FDA News Release, 14 May 2013 side effects included rash, diarrhea, at http://www.fda.gov/NewsEvents/Newsroom/ peripheral edema and skin breakouts that PressAnnouncements resemble acne.

Dabrafenib, trametinib and Women of child bearing years should companion diagnostic test for be advised that Tafinlar® and Mekinist® advanced skin cancer carry the potential to cause foetal harm. Men and women should also be advised United States of America — The Food that these products carry the potential to and Drug Administration (FDA) has cause infertility. approved two drugs, dabrafenib (Tafin- lar®) and trametinib (Mekinist®), for Reference: FDA News Release, 29 May patients with metastatic or unresectable 2013 at http://www.fda.gov/NewsEvents/ melanoma. Newsroom/PressAnnouncements/ucm354199. htm?source=govdelivery Tafinlar®, a BRAF inhibitor, is approved to treat patients with melanoma whose Cysteamine bitartrate approved tumours express the BRAF V600E gene for rare genetic condition mutation. Mekinist®, a MEK inhibitor, is approved to treat patients whose tumors United States of America — The express the BRAF V600E or V600K gene Food and Drug Administration (FDA) mutations. Approximately half of mela- has approved cysteamine bitartrate nomas arising in the skin have a BRAF (Procysbi®) for the management of gene mutation. They are being approved nephropathic cystinosis in children and as single agents, not as a combination adults. treatment. Cystinosis is a rare genetic condition that The FDA has approved Tafinlar® and affects an estimated 500 patients in the Mekinist® with a genetic test called United States and about 3000 patients the THxID BRAF test®, a companion worldwide. Cystinosis may lead to slow diagnostic that will help determine if a body growth and small stature, weak patient’s melanoma cells have the V600E bones and developing and worsening or V600K mutation in the BRAF gene. kidney failure.

The most serious side effects reported in The most common side effects include patients receiving Tafinlar® included an nausea, bad breath, abdominal pain, increased risk of cutaneous squamous constipation, indigestion or upset cell carcinoma, fevers that may be com- stomach, headache, drowsiness and plicated by hypotension, severe rigors, dizziness. Other uncommon but serious dehydration, kidney failure and increased side effects include ulcers or bleeding of blood sugar levels requiring changes in the stomach or intestine, altered mental diabetes medication or the need to start state, seizures, severe skin rashes and medicines to control diabetes. The most allergic reactions.

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Reference: FDA News Release, 30 April 2013 Additionally, because original OxyContin® at http://www.fda.gov/Drugs/NewsEvents/ provides the same therapeutic benefits as reformulated OxyContin®, but poses Fluticasone furoate and vilanterol an increased potential for certain types approved for chronic obstructive of abuse, the FDA has determined that pulmonary disease the benefits of original OxyContin® no longer outweigh its risks and has been United States of America — The withdrawn from sale. Accordingly, the Food and Drug Administration (FDA) agency will not accept or approve any has approved fluticasone furoate and abbreviated new drug applications vilanterol inhalation powder (Breo (generics) that rely upon the approval of Ellipta®) for the long-term, once-daily, original OxyContin®. maintenance treatment of airflow obstruction in patients with chronic The reformulated tablet is more difficult obstructive pulmonary disease (COPD), to crush, break, or dissolve. It also forms including chronic bronchitis and/or a viscous hydrogel and cannot be easily emphysema. It is also approved to reduce prepared for injection. exacerbations of COPD in patients with a history of exacerbations. Reference: FDA News Release, 16 April 2013 at http://www.fda.gov/NewsEvents/Newsroom/ The drug carries a boxed warning that PressAnnouncements/ucm348252.htm long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma- Imatinib approved for leukaemia related death. The safety and efficacy European Union — The Committee of Breo Ellipta® in patients with asthma for Medicinal Products for Human Use have not been established, and it is not (CHMP) has recommended granting of approved for the treatment of asthma. a marketing authorization for imatinib (Imatinib Accord®), film-coated tablet Breo Ellipta® may cause serious side 100 mg and 400 mg intended for the effects, including increased risks of treatment of leukaemia. pneumonia and bone fractures. The most common side effects reported included Imatinib is a small molecule protein- nasopharyngitis, upper respiratory tract tyrosine kinase inhibitor that potently infection, headache, and oral candidiasis. inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor Reference: FDA News Release, 10 May 2013 TKs. Imatinib Accord® is indicated for the at http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements treatment of: • Paediatric patients with newly Oxycodone with abuse-deterrent diagnosed Philadelphia chromosome properties approved (bcr-abl) positive (Ph+) chronic United States of America — The myeloid leukaemia (CML) for whom Food and Drug Administration (FDA) bone marrow transplantation is not has approved updated labelling for considered as the first line of treatment. reformulated oxycodone hydrochloride • Paediatric patients with Ph+ CML in controlled-release tablets (OxyContin®). chronic phase after failure of interferon- The new labelling indicates that the alpha therapy, or in accelerated phase product has physical and chemical or blast crisis. properties that are expected to make abuse via injection difficult and to reduce • Adult patients with Ph+ CML in blast abuse via the intranasal route. crisis.

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Reference: EMA Press Release, EMA/ However, before now, A1c tests were 250071/2013. 25 April 2013 at http://www. not specifically designed or granted ema.europa.eu/ema/index.jsp?curl=pages/ permission by FDA to be marketed for news_and_events/news/2013/04/news diabetes diagnosis, making it difficult to know which A1c tests were accurate First A1c test labelled for enough for this purpose. The Tina-quant diagnosing diabetes HbA1cDx assay, a laboratory-based test, can be used to both accurately diagnose United States of America — The Food diabetes and monitor blood glucose and Drug Administration (FDA) has control. announced that it is allowing marketing of the Tina-quant HbA1cDx assay Over-the-counter HbA1c tests should (Cobas Integra 800 Tina-quant HbA1cDx not be used by patients to diagnose assay®) for the diagnosis of diabetes by diabetes, and only a qualified health care healthcare professionals. professional should make a diagnosis of diabetes. Individuals who receive a The HbA1c tests, or A1c tests, currently diabetes diagnosis should discuss with on the market are FDA-cleared for their physician what they need to do to monitoring a patient’s blood glucose manage their diabetes. control, but not for diagnosing diabetes. A1c tests measure the percentage of Hemoglobin A1c tests, including the hemoglobin A1c that is bound to glucose, Tina-quant HbA1cDx assay, should giving a patient’s average glucose level not be used to diagnose diabetes over a three-month period. during pregnancy and should not be used to monitor diabetes in patients The diagnostic criteria for diabetes with hemoglobinopathy, hereditary have changed over time. Based on spherocytosis, malignancies, or severe the research and recommendations of chronic, hepatic and renal disease. This international diabetes experts, many test should not be used to diagnose or health care providers have already monitor diabetes in patients with the been using some A1c tests to diagnose hemoglobin variant hemoglobin F. diabetes, in addition to the established diagnostic procedures of a fasting Reference: FDA News Release, 23 May 2013 blood glucose test and an oral glucose at http://www.fda.gov/NewsEvents/Newsroom/ tolerance test to diagnose diabetes. PressAnnouncements

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The International Pharmacopoeia

International Meeting Compared to national and regional pharmacopoeias, The International of World Pharmacopoeias Pharmacopoeia (Ph. Int.) is issued by A pharmacopoeia is a legally binding WHO as a recommendation with the collection of standards and quality aim of providing international standards specifications for medicines used – including less technically demanding in a country or region. Within the alternatives where needed — for pharmacopoeia, a quality specification is adoption by Member States and to help a set of appropriate tests that will confirm achieve a potentially global uniformity the identity and purity of the product, of quality specifications for selected ascertain the strength (or amount) of the pharmaceutical products, excipients and active substance and, when needed, the dosage forms. performance characteristics. Reference substances are used in testing to help In response to a call for input, and ensure the quality, such as identity, as follow-up to discussions with strength and purity, of medicines. representatives of world pharmacopoeias during the International Conference of A pharmacopoeia also covers pharma- Drug Regulatory Authorities in Hong ceutical starting materials, excipients, Kong in 2002 and in Madrid in 2004, intermediates and finished pharma- WHO organized the International Meeting ceutical products (FPPs). General of World Pharmacopoeias in early requirements may also be given on 2012. The aim was to discuss topics of important subjects related to medicines common interest and address identified quality, such as analytical methods, challenges. microbiological purity, dissolution testing, or stability (1). In order to prepare for the meeting, WHO provided a set of preliminary The role of a modern pharmacopoeia questions on pharmacopoeias to meeting is to furnish quality specifications for participants in an effort to inspire input to active pharmaceutical ingredients (APIs), the agenda. The questions, presentations FPPs and general requirements. The and final report are now available on a existence of such specifications and dedicated web site (3). This article is a requirements is necessary for the proper summary of the report. functioning or regulatory control of medicines production. Pharmacopoeial Pharmacopoeia: publication and requirements form a basis for establishing frequency of updates quality requirements for individual The pharmacopoeia, as a public tool, pharmaceutical preparations. maintains quality of medicines by collecting the recommended procedures According to the information available for analysis and specifications for to the World Health Organization the determination of pharmaceutical (WHO), 140 independent countries are substances, excipients and dosage at present employing thirty national forms and, in most cases, consists of a as well as African, European and general part (tests, methods and general International Pharmacopoeias (2). requirements) and a specific part in the

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Questions proposed to pharmacopoeias

1. Name of pharmacopoeia. 2. Is pharmacopoeia referred to in national/regional legislation – if yes, which? 3. Does national/regional legislation make reference to other national, regional, or internatio- nal pharmacopoeias(s) – if yes, which? 4. When was publication of latest edition?

5. What is the update frequency – annually, biannually, other (please specify). 6. For which products does the pharmacopoeia provide specifications?APIs, dosage forms, herbal products, biologicals, traditional medicines, etc. (please specify) 7. What number of texts are included in the pharmacopoeia monographs for APIs, finished dosage forms, biologicals, and general monographs? 8. Is there collaboration with and/or being part of a (different) national/regional pharmaco- poeia – if yes, which? 9. Is there publication of harmonized pharmacopoeial texts within the pharmacopoeia if yes, which pharmacopoeia, which type, how many? 10. Interaction with stakeholders, including regulators? 11. What is the strategy for the future? form of monographs for pharmaceutical Legal basis and references substances. Pharmaceutical analysis to other pharmacopoeias represents a platform through which Pharmacopoeias are referred to in state-of-the-art research can affect the legislation which confirms their legally quality, safety and efficacy of medicines binding status in the relevant country or directly by pharmacopoeial application of region. scientific results into everyday practice. In Europe, a regional approach is used. Transparency and scientific progress the European Pharmacopoeia (Ph. are the driving forces behind the need to Eur.) was created by eight Member constantly update all pharmacopoeias. States in 1964 and today consists of Discussion of internationalization 36 Member States and the European and unifying principles for the quality Union (EU) which are signatories to of medicines will require mindful the Convention on the Elaboration of consideration of the different languages a European Pharmacopoeia. Ph. Eur. and medicines regulatory activities members are: Austria, Belgium, Bosnia among countries. and Herzegovina, Bulgaria, Croatia, Most pharmacopoeial commissions take Cyprus, Czech Republic, Denmark, measures to update their pharma- Estonia, Finland, France, Germany, copoeias in a timely manner. The Greece, Hungary, Iceland, Ireland, Italy, updates are performed through the Latvia, Lithuania, Luxembourg, (the publication of supplements and addenda former Yugoslav Republic of) Macedonia, or by partial revision. More than half Malta, Montenegro, Netherlands, Norway, the pharmacopoeias represented at the Poland, Portugal, Romania, Serbia, meeting are updated annually. Slovakia, Slovenia, Spain, Sweden,

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Switzerland, Turkey, United Kingdom, pharmacopoeia is also accepted in and the EU. In addition, there are 24 legislation for Brazil and other countries observers, comprising 23 countries and where Portuguese is an official language. WHO. WHO’s International Pharmacopoeia EU Directives stipulate that ″the (Ph. Int.) is «ready for use» by Member monographs of the European States. The Ph. Int. is referred to in a Pharmacopoeia shall be applicable number of national legislations due to its to all substances, preparations and applicability. pharmaceutical forms appearing in it. In respect of other substances, each For which products does Member State may require observance of the pharmacopoeia provide its own national pharmacopoeia.″ These specifications? directives are transposed into national A large number of products are usually legislation of EU Member States. covered, reflecting the diligence and commitment of pharmacopoeial Some of the 36 Member States of the authorities and their appointed experts Ph. Eur. Convention have decided to develop a comprehensive working to discontinue their own national tool with up-to-date scientific data. pharmacopoeia and use only the Ph. Eur. The complexity and diversity of most Examples are Sweden and Finland. pharmacopoeias results from mutual Other Member States of the Ph. Eur. integration and interdependence with Convention have decided to continue monographs for various types of products their national pharmacopoeia for products such as active pharmaceutical ingredients of solely national interest. In Switzerland, (APIs), excipients, herbal products, for instance, the Pharmacopoea Helvetica biologicals (vaccines, blood products), (Ph. Helv.) exists alongside the Ph. Eur. radiopharmaceuticals, dosage forms and and the two together form the legally homeopathic preparations. binding pharmacopoeia. In France, the pharmacopoeia consists of the texts of It may be noted that there is a majority of the European Pharmacopoeia and of finished dosage forms, which generally the French Pharmacopoeia, including can be defined as the form of active the ″overseas″ pharmacopoeia. Other ingredient which is or is intended to be countries, such as the United Kingdom, dispensed or administered to the patient have decided to fully integrate the and requires no further manufacturing texts of the Ph. Eur. into their national or processing other than packaging pharmacopoeia; hence the British and labelling. This is in parallel to Pharmacopoeia (BP) contains the texts the decreasing tendency of specific of the Ph. Eur. in addition to the national national monographs for APIs within texts of the BP. some national pharmacopoeias due to replacement with monographs from National/regional legislation often regional or international pharmacopoeias. includes reference to other pharmaco- poeias in the event that their own As the pharmacopoeia itself has pharmacopoeial texts are not available. emerged from experience gained Thus the EU pharmaceutical legislation throughout the centuries, the roots of and hence the legislation of all EU this valuable knowledge can still be seen Member States includes references both in contemporary medicine as traditional at the national/regional and international medicine monographs, represented levels. Historic and language ties also mainly in the pharmacopoeias of China, play a role. For example, the Portuguese France (overseas), Japan and Ph. Eur.

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Likewise, homeopathic approaches are of participation occur. Active participants, represented in pharmacopoeias in Brazil, such as members of Ph. Eur., can Germany and Mexico, for example. contribute their share of pharmacopoeial development, while passive forms of The pharmacopoeias reviewed at participation may include observational the International Meeting of World missions to benefit from the experience of Pharmacopoeias contain standards for other countries in specific areas and gain chemical and biological drug substances, access to the work on quality control of dosage forms, compounded preparations, medicines and methods of analysis used. excipients, medical devices and dietary supplements. During the current Leading world pharmacopoeias promote meeting some countries, such as Brazil, constant progress within pharmacopoeial France, Germany, Mexico, Serbia and development, ″good pharmacopoeia Switzerland, provided examples of practice″ and recommendations of incorporating a national formulary for procedures for analysis intended to hospital and/or community pharmacy serve as source material for reference or preparations into their pharmacopoeias. adaptation by any of their Member States In Portugal, there is a non-official national wishing to establish pharmaceutical formulary which is published by the requirements. Portuguese Pharmacies Association. During the meeting, examples were given Ph. Int. provides an opportunity of types of monographs with less frequent to comment on drafts by all world occurrence than other types. pharmacopoeias and offers participation in meetings, such as consultations and For example, monographs for blood Expert Committees during the WHO products were presented by Argentina consultation process. There are also (12), Brazil (20) and India (21), while WHO special projects covering quality monographs for vaccines were presented assurance of medicines worldwide, by Argentina (21), India (57), Kazakhstan such as collaboration with the African (15) and Ukraine (26). Homeopathic Pharmacopoeia, British Pharmacopoeia, preparations described in monographs Chinese Pharmacopoeia, Council of were presented mainly by France Europe/Ph. Eur. and the Pharmacopoeial (320), Germany (120) and Mexico (558) Discussion Group (PDG). and finally monographs for traditional medicine were given as an example Ph. Eur. covers all national pharmaco- by China (2165). A total of 92 herbal, poeias of the signatory parties to the traditional herbal and homeopathic Convention, who are members of the monographs are present in the British Ph. Eur. with emphasis on complement- Pharmacopoeia 2012. Supplementary arity, thereby reducing duplication of information is included in some of the work. In some member countries of pharmacopoeias, for example general the Ph. Eur. national pharmacopoeias texts, reference tables, and texts on complement the Ph. Eur. for texts of methods of analysis, reagents, materials/ interest to one Member State only. containers, sutures, and reference Some member countries also republish substances used in national monographs. Ph. Eur. monographs in their national pharmacopoeias. Membership and Collaboration among observership enables States to pharmacopoeias participate in Ph. Eur. Commission Pharmacopoeial authorities collaborate at sessions even if only Members are both regional and international levels for entitled to vote. Within these sessions, the sake of harmonization and exchange each Member State is represented by its of experience. Active and passive forms national delegation consisting of not more

122 WHO Drug Information Vol. 27, No. 2, 2013 The International Pharmacopoeia than three members. On all technical collaboration of the Czech Republic matters delegations cast a vote. The EU with the Slovak Republic results from decides on behalf of EU Member States a common history. Agreements for in all non-technical issues of the Ph. Eur. collaboration have been signed between Each Member State and observer can countries to increase the degree of also propose national experts for each compatibility, such as the USP with group of experts or working party. Mexico. Ukraine has also signed a collaborative agreement with USP, while The European Medicines Agency intensively working with Kazakhstan. A (EMA) participates in the sessions of memorandum of understanding has been the Ph. Eur. Commission and working signed by both the British Pharmacopoeia parties of interest. The European (BP) and Ph. Int. to use and incorporate Directorate for the Quality of Medicines developed monographs mutually. and HealthCare (EDQM) participates in relevant committees and working parties Intensive collaboration with China’s at the level of the EMA alongside national pharmacopoeial authorities was competent authorities. In addition, annual described by representatives of the meetings are organized between EDQM British and French Pharmacopoeias and national pharmacopoeial authorities. and USP during the meeting. France Thirty-six Member States and the EU collaborates with Algeria, Morocco are signatories to the Convention on and Tunisia due to the fact that the the Elaboration of a European Pharmaco- French language is used in those poeia. pharmacopoeias. Brazil and Viet Nam Observership to the Ph. Eur. allows for are also named as collaborators with the participation in the scientific work of the French Pharmacopoeia. In information European Pharmacopoeia Commission. sent to WHO, Korean pharmacopoeial Observer examples are Belarus, Brazil, representatives mentioned bilateral China, Russia, the United States of memoranda of understanding with America, and WHO. Ph. Eur. and USP. The Pharmacopoeial Discussion Group Publication of harmonized (PDG) consists of representatives pharmacopoeial texts within of three pharmacopoeias: Ph. Eur., the pharmacopoeia Japanese Pharmacopoeia (JP) and The PDG has defined harmonization of the United States Pharmacopoeal a pharmacopoeial monograph or general Convention (USP). Its main activities are chapter as follows: retrospective harmonization of general chapters and excipient monographs. In ″A pharmacopeial general chapter addition, Ph. Eur. and USP are running a or other pharmacopeial document is pilot project on prospective harmonization harmonized when a pharmaceutical of active pharmaceutical ingredient substance or product tested by the monographs. document’s harmonized procedure yields the same results and the same accept/ MERCOSUR, as an example of intensive reject decision is reached.″ (4). collaboration at the regional level, and is formed by Argentina, Brazil, When using a fully harmonized pharma- Paraguay and Uruguay. Texts and copoeial monograph or general chapter, chapters are discussed for inclusion in an analyst will perform the same the MERCOSUR Pharmacopoeia. procedures and reach the same accept/ reject decisions irrespective of which Some collaboration is historically and PDG pharmacopeia is referenced. geographically related. Traditional This is called interchangeability and

123 The International Pharmacopoeia WHO Drug Information Vol. 27, No. 2, 2013 each pharmacopoeia identifies, in texts in the USP-NF, where 41 of 61 of an appropriate manner, each fully excipient monographs and 28 of 35 of harmonized monograph and general general chapters have been harmonized chapter. so far. The realization that it was important Latin America to have an independent evaluation of Countries participating within medicinal products before they are MERCOSUR have included harmonized allowed on the market was reached texts in their national pharmacopoeias at different times in different regions. after discussion. PDG texts are also In many cases action was driven by considered during discussions of the tragedies, such as that with sulfanilamide Brazilian Pharmacopoeia Committee. in the USA in 1937 and with thalidomide Mexico does not have a formal process in the 1960s. Therefore, the urgent need for the harmonization of information to rationalize and harmonize regulation with other pharmacopoeias, but its drug was impelled by concerns over rising monographs are consistent in their costs of health care, escalation of the specifications with the BP, Ph. Eur. and cost of research and development and USP in 60–100%. the need to meet public expectations for a minimum delay in making safe and Ph. Int. collaborates worldwide and has efficacious new treatments available to texts harmonized from various sources patients in need. due to its rich collaboration. With the British Pharmacopoeia, this resulted in Eastern Europe three texts adopted in 2010, with 19 in The majority of the State Pharmacopoeia the pipeline. Also, through collaboration of the Republic of Kazakhstan is with PDG, 12 general methods were formed from harmonized texts, including adopted in Ph. Int. in 2011 with more in general chapters and monographs, mono- the pipeline for methods of analysis and graphs on pharmaceutical substances, supplementary information. monographs on vaccines for human use and human immunoglobulins. In the Interaction with stakeholders, Ukrainian Pharmacopoeia Supplement, including regulators there are seven harmonized monographs There are many ways for national/ for finished dosage forms, four are regional pharmacopoeial authorities pursuant to the ″Grant of Rights to Copy to interact and be influenced by and Adapt the USP-NF ″ contract. Eleven stakeholders, particularly through public draft monographs for the 2nd Edition forums. have already been elaborated. The most common interactions are at national level between national and Asia regional regulatory authorities, quality Japan contributes to harmonization control laboratories and different efforts with its counterparts – Ph. Eur. institutions related to quality assurance of and USP – within the PDG and the medicines. Fusion of academic, clinical Japanese Pharmacopoeia contains and industrial fields, such as universities general tests (14), general information and other academic bodies, hospital (11) and excipient monographs (31) and community pharmacies organized as harmonized texts. The Korean in expert groups, and manufacturers Pharmacopoeia has harmonized PDG worldwide through their organizations, texts for general tests. represent a platform for comprehensive and progressive discussion. North America USP incorporates PDG-harmonized To enable harmonization and a reliable

124 WHO Drug Information Vol. 27, No. 2, 2013 The International Pharmacopoeia source of fluid information exchange Ph. Int. specifications. Keeping the costs at the global level, international of analysis in mind, especially in the case organizations (UNAIDS, UNFPA, of developing countries, Ph. Int. provides UNICEF, World Bank, WIPO, WTO, standards for major public health needs. WCO), international professional and other associations, nongovernmental Regional organizations (FIP, IFPMA, IGPA, MSF, Ph. Eur. supports innovation and WMA, WSMI), quality control laboratories flexibility without losing the aim of a (other than national/regional), United pharmacopoeia to provide official, Nations-related organizations such as the recognized and technically sound quality Global Fund to Fight AIDS, Tuberculosis standards. It also remains at the forefront and Malaria, and WHO programmes in the biofield and constantly increases including International Nonproprietary pharmacopoeial harmonization through Names, Prequalification of Medicines, collaboration, i.e. as part of PDG, Medicines Regulatory Support, Medicines and maintains observers within other Safety, Traditional Medicines, Quality, pharmacopoeial institutions worldwide. Safety and Standards and specific Ph. Eur. Member States Sweden and disease programmes, are all stakeholders Finland continue to cooperate and be in collaboration. active in the elaboration of the Ph. Eur.

Specific harmonization issues are National discussed within regional and inter- Croatia is currently preparing a regional harmonization groups (ASEAN, publication of a new edition of the GCC, ICH, PANDRH, SADC, etc.). Croatian Pharmacopoeia. To ensure discussion and pragmatic approaches, annual science and standard The Czech Republic would like to symposia are organized, as well as public complete a national formulary, mainly in forums, for an unbiased outside view on the field of paediatrics through coopera- particular issues. tion with the chamber of paediatricians. Assessment of stability in the pharmaco- Strategy for the future poeia formularies for small-scale products Strategies of the individual pharmaco- and products prepared in pharmacies poeias differ for geographical and have also been mentioned as a future economic reasons and depending on the plan by Czech representatives, as well as level of integration to respective regional establishment of a new group of experts international systems. There was a from hospital pharmacies and certified commitment to establish comprehensive, laboratories. updated editions with highly compatible standards at a national or regional France presented its strategy for the level, as well as intentions to harmonize future at both the national and European intensively with emphasis on increased levels. Publication online will define new quality assurance of medicines around policy and reinforce the code of practice the world. in line with the new French Public Health Law. France defines the work programme International based on both interest of patients or pro- Ph. Int. commits to fulfilling the mandate fessionals (paediatric, ophthalmic and of WHO given by its Member States and homeopathic preparations) and conforms responds to the needs of the latter. As to regulation and national strategy an international body, it also responds to (French overseas territories). As a key the needs of quality control laboratories player within the Ph. Eur., France would for post-marketing surveillance and like to contribute to specific topics maintains the international applicability of such as biological products, cell

125 The International Pharmacopoeia WHO Drug Information Vol. 27, No. 2, 2013 and tissue therapies, anti-allergenic corresponding monographs of the leading products, antiseptic preparations, world pharmacopoeias. This will be paediatric preparations, traditional herbal assisted by participation of the Federal preparations and collaboration with P4 State Budgetary Institution “Scientific procedures. Centre for Expert Evaluation of Medicinal Products” of the Ministry of Health of the In addition to its contribution to the Russian Federation in the work of the Ph. Eur., Germany focuses on particular WHO Expert Committee on Specifications technical issues in terms of pharma- for Pharmaceutical Preparations, work ceutical analysis such as identification of of the EDQM (as an observer) and work materials by the evaluation of analytical of the WHO Working Group on Good fingerprinting, use of non-destructive Pharmacopoeial Practices. spectroscopic methods, imaging techniques for the intact pharmaceutical United Kingdom representatives preparations, trace analysis of impurities presented priorities at the international and simplified analytical identification level. Contributions and intensive tests for certified substances. collaboration within the Ph. Eur. were also described. National activities of As a country collaborating closely with the BP will focus on the Annual BP and the Ph. Eur., Portugal is focusing on its BP (Vet) Publications, British Approved future plan to update national texts and Names Supplements, increase in New to tighten the links with Portuguese- Formulated Preparation Monographs speaking countries and stakeholders. (licensed and unlicensed), Supplementary Serbia will prepare its national addition Chapters for BP and BP (Vet), Red Tape to Ph. Eur., update national ″Magistral Challenge, Stakeholder Cooperation Formularies″ and continue cooperation (manufacturers, practition- with the Ph. Eur. ers, pharmacies, etc.) and tailored publications. Spain plans to follow the timetable for publication of the in-force Ph. Eur. Japan‘s efforts toward internationalization successive editions (simultaneous of its pharmacopoeia are based on translation), to work with internal prompt publication and further improve- Spanish groups that support work of the ment of the JP English edition and experts and specialists in European and web site. Building up the framework for international groups and continue its international information exchange among efforts to cooperate with the work of the pharmacopoeias will also be intensified. Ph. Eur. and international groups. For its next revision JP commits itself to follow-up of the revision of ″General Switzerland focuses on participation Rules for Preparations ″ in JP16: general in the activities of the Ph. Eur. in the quality tests for preparations would framework of the legally binding mandate be newly set, containers and storage of the Ph. Eur. Convention. section revised, and a new framework Introduction of quality standards of the for monographs of drugs created whose Russian Federation Pharmacopoeia manufacturing processes are different, (SP RF) 12th edition (Vols 1–5) in the including impurities (including residual territory of the Russian Federation, solvents), process-related substances, development of new quality standards impurities in biotechnology products and for medicinal products and review of tests for preparations. the older ones, will help to upgrade the national regulatory system. Plans for China provided information to WHO the future also include harmonization stating that the country is committed to of the SP RF monographs with the more cooperation with other world leading pharmacopoeias.

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poeial Commission are strengthening India, in terms of sharing of information of regional harmonization through joint among pharmacopoeias, would like to development of reference standards and focus on resources, working in pockets harmonization of general methods and where there is a need for sharing informa- monographs in order to establish similar tion and providing commitment to quality standards within the region. monitoring, harmonizing with leading pharmacopoeias. Provision of quality Brazil commits to continuing its integra- medicines will be improved through tion with the MERCOSUR Pharma- harmonized drug standards and copoeia and aligning the Brazilian monitoring the quality of medicines Pharmacopoeia with public health needs through an effective regulatory system. and public policy development.

Indonesia’s plans are to publish a new Mexico wants to stay tuned to the needs edition of the Indonesian Pharmacopoeia of the health authority and users, to every five years, to publish the supple- maintain its current pharmacopoeia, ment annually for the existing pharmaco- continue promoting the approach of poeia and to publish the pharmacopoeia users to participate in the development in an English version. of monographs and establish closer Korea has informed WHO that it aims communication with colleagues in other to include in its pharmacopoeia all parts of the world. medicines which are relevant from the viewpoint of health care and medical North America treatment. It will revise it in a timely USP strategy focuses on creating manner for more efficient application and monographs in ways that rely on both will follow international harmonization. the traditional donor model as well Transparency will be important in revision as on research and development in of the Korean Pharmacopoeia, and the its own laboratories. In support of the document will be publicly available and second approach, USP has created the include up-to-date analytical methods and Medicines Compendium (MC), a freely preparation of reference standards. available, online-only compendium of public standards for medicines approved Eastern Europe in any country. The MC monographs A future strategy for Kazakhstan will provide performance tests for critical include the introduction of the State quality attributes and acceptance Pharmacopoeia, further harmonization criteria, a source-independent reference with Ph. Eur. and USP and development, procedure and one or more acceptable edition and revision of its own mono- procedures submitted by manufacturers. graphs. The MC strives to make available Ukraine would like to transform its reference materials for all possible status from observer at the Ph. Eur. impurities associated with a particular Commission to membership, support monograph, and to expand approaches leading pharmacopoeias and implement to include USP-NF, where many harmonized standards. It aims to facilitate monographs are missing and more need the movement of high-quality medicines updating. USP is also strengthening through developing pharmacopoeial its ability to develop impurity reference educational programmes and expanding materials independently through synthetic visiting scientist programmes. capabilities. Latin America In addition, USP is working on The priorities for Argentina’s Pharmaco- standards with allied activities in

127 The International Pharmacopoeia WHO Drug Information Vol. 27, No. 2, 2013 support of manufacturers, regulatory including analytical fingerprinting, non- bodies and others. Examples include destructive spectroscopic methods and a ″global comparator product″, as well imaging. Lastly, support was reiterated as emphasis on biological medicines for maintenance of the international standards in support of new, biosimilar applicability of Ph. Int. specifications. and interchangeable biological products. Individual presentations, the full report USP is working on spectral imaging and conclusions are to be found on the approaches that allow field approaches WHO web site (3). to assure identity. These latter efforts align with the more elaborate laboratory References testing approaches in a pharmacopoeial 1. Kopp, S. The International Pharmacopoeia monograph or a private specification. – a Myth or Reality? International Pharmacy Journal. 2006, 20 (2). Conclusion Participants at the meeting agreed to 2. Index of Pharmacopoeias at http://www. focus in the future on acceleration of who.int/medicines/areas/quality_safety/ international harmonization between quality_assurance/resources/index-of- pharmacopoeias16032012.pdf. world pharmacopoeias, and also on the establishment of an international bank 3. WHO Medicines Quality Assurance of harmonized texts for substances Programme. Review of World Pharmaco- and finished dosage forms of the most poeias, WHO/QAS/12.512/Rev.1 at http:// common vital medicines. It was also www.who.int/medicines/areas/quality_safety/ agreed that there should be a build-up of quality_assurance/resources/qas frameworks for international information _worldpharmmeeting/en/index.html. exchange among pharmacopoeias, 4. Harmonization – Pharmacopoeial an introduction of new techniques, Discussion Group (PDG) at http://www.usp. org/usp-nf/harmonization

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Recent Publications, Information and Events

Consortium to test kala-azar Africa with vast experience in R&D and treatments in East Africa treatment of HIV and kala-azar, namely the Drugs for Neglected Diseases The research and development project, initiative (DNDi); the Institute of Tropical AfriCoLeish, will run for three years and Medicine (ITM) in Antwerp; the London aims to test new treatments for kala- School of Hygiene & Tropical Medicine; azar (visceral leishmaniasis, or VL) and Medecins Sans Frontieres (MSF, The co-infection of the disease with HIV in Netherlands); the Institute of Endemic Ethiopia and Sudan. Diseases, University of Khartoum (IEND), Sudan; and the University of Gondar The AfricoLeish project, Care Package (UoG), Ethiopia. for Treatment and Control of Visceral Leishmaniasis in East Africa, aims to Reference: DNDi Press Release, 23 April develop and deliver a shorter combination 2013 at http://www.dndi.org and http://www. treatment for kala-azar patients that is as africoleish.org and www.africoleish.org safe and effective as the current WHO- recommended first-line treatment of New guide to improve sodium stibogluconate and paromomycin procurement performance (SSG&PM). The project also aims to determine appropriate treatment The USAID Deliver Project has published strategies for kala-azar patients who three new documents that can help are also HIV positive, in order to treat supply chain programme managers and prevent repetitive relapses that are understand and track key performance common in co-infected patients. indicators for the procurement process. The Procurement Performance Indicators Kala-azar is fatal if left untreated. An Guide Using Procurement Performance estimated 300,000 cases occur per Indicators to Strengthen the Procurement year in 70 endemic countries. Estimates Process for Public Health Commodities suggest there are 30,000 new cases describes suggested key indicators that per year in Africa, with numbers rising can be helpful in tracking various aspects sharply during an epidemic. Existing of a procurement system. monotherapies are toxic, costly, and difficult to administer, and the treatment The guide is intended for procurement duration is long, requiring extended managers at ministries of health and cen- hospital stays. Efficacious and cost- tral medical stores who are responsible effective treatments as well as prevention for procuring public health commodities. of relapse play a critical role in the It is complemented by the Procurement reduction of disease reservoirs, and form Performance Indicators Dashboard, a a vital part of disease control. In addition, Microsoft Excel spreadsheet that cap- co-infection of kala-azar and HIV is a tures performance data and graphically growing problem and renders treatment summarizes results for each indicator in a more difficult for both diseases. dashboard format. AfriCoLeish brings together six Reference: USAID Deliver Project at http://j. organizations from Europe and East mp/ZPPcRl and http://deliver.jsi.com/

129 WHO Drug Information Vol. 27, No. 2, 2013

ATC/DDD Classification

ATC/DDD Classification (Temporary)

The following anatomical therapeutic codes (ATC), defined daily doses (DDD) and alterations were considered by the WHO International Working Group for Drug Statistics Methodology at its meeting in March 2013. Comments or objections to the decisions should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology at [email protected]. The new ATC codes, DDDs and alterations will then be considered final and be included in the January 2014 version of the ATC/DDD index. The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy.

New ATC 5th level codes:

ATC level INN/Common name ATC code

afamelanotide D02BB02 apremilast L04AA32 brimonidine D11AX21 calcium citrate A12AA13 carfilzomib L01XX45 colestilan V03AE06 delamanid G04AK06 dienogest and ethinylestradiol G03AA16 eliglustat A16AX10 empagliflozin A10BX12 encephalitis, Japanese, live attenuated J07BA03 formoterol and fluticasone R03AK11 insulin degludec A10AE06 insulin degludec and insulin aspart A10AD05 lamivudine, tenofovir disoproxil and efavirenz J05AR11 macitentan C02KX04 metformin and dapagliflozin A10BD15 nalmefene N07BB05 naloxegol A06AH03 nomegestrol and estrogen G03FB12 obinutuzumab L01XC15 ocriplasmin S01AX22 ospemifene G03XC05

Continued/

130 WHO Drug Information Vol. 27, No. 2, 2013 ATC/DDD Classification

ATC level INN/Common name ATC code pomalidomide L04AX06 serelaxin C01DX21 strontium ranelate and colecalciferol M05BX53 sucroferric oxyhydroxide V03AE05 technetium (99mTc) tilmanocept V09IA09 tolperisone M02AX06 vortioxetine N06AX26

Change of ATC code: INN/Common name Previous ATC code New ATC code

bromelains B06AA11 D03BA03

Change of ATC level names: Previous New ATC code

nabiximols cannabinoids N02BG10 Insulins and analogues for injection, Insulins and analogues for intermediate-acting combined with injection, intermediate- or long- fast-acting acting combined with fast-acting A10AD Other oxytocics Other uterotonics G02AX Antiprogestogens Progesterone receptor modulators G03XB Oxytocics Uterotonics G02A

New DDDs:

DDD unit Adm.R ATC code

aclidinium bromide* 0.644 mg Inhal powder R03BB05 bedaquiline 86 mg O J04AK05 ceftaroline fosamil 1.2 g P J01DI02 dapagliflozin 10 mg O A10BX09 glycopyrronium bromide** 44 mcg Inhal powder R03BB06 mannitol 0.8 g Inhal poweder R05CB16 mirabegron 50 mg O G04BD12 perampanel 8 mg O N03AX22 tafamidis 20 mg O N07XX08 teriflunomide 14 mg O L04AA31 ulipristal 5 mg O G03XB02

* refers to aclidinium, delivered dose ** refers to glycopyrronium, delivered dose

131 WHO Drug Information Vol. 27, No. 2, 2013

ATC/DDD Classification

ATC/DDD Classification (Final)

The following anatomical therapeutic codes (ATC), defined daily doses (DDD) and alterations were agreed by the WHO International Working Group for Drug Statistics Methodology at its meeting in October 2012. These ATC codes, DDDs and alterations are considered asfinal and will be included in the January 2014 version of the ATC/DDD index. The WHO Collaborating Centre for Drug Statistics Methodology can be contacted at [email protected] The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy.

New ATC 5th level codes:

ATC level INN/Common name ATC code

lorcaserin A08AA11 metformin and repaglinide A10BD14 gemigliptin A10BH06 lixisenatide A10BX10 canagliflozin A10BX11 ethacizine C01BC09 meldonium C01EB22 amlodipine and diuretics C08GA02 perindopril, amlodipine and indapamide C09BX01 candesartan and amlodipine C09DB07 rosuvastatin and ezetimibe C10BA06 rosuvastatin and acetylsalisylic acid C10BX05 ulipristal G03XB02 levofloxacin, combinations with other antibacterials J01RA05 bedaquiline J04AK05 dolutegravir J05AX12 vintafolide L01CA06 trastuzumab emtansine L01XC14 dabrafenib L01XE23 ponatinib L01XE24 trametinib L01XE25 aflibercept L01XX44 cridanimod L03AX18 teriflunomide L04AA31 phenibut N06BX19

Continued/

132 WHO Drug Information Vol. 27, No. 2, 2013 ATC/DDD Classification

ATC level INN/Common name ATC code

mebicar N06BX21 ipidacrine N06DA05 dimethyl fumarate N07XX09 laquinimod N07XX10 olodaterol R03AC19 vilanterol and fluticasone furoate R03AK10 vilanterol and umeclidinium bromide R03AL03 indacaterol and glycopyrronium bromide R03AL04 cineole R05CA13 sequifenadine R06AX32 mercaptamine S01XA21 technetium (99mTc) etarfolatide V09IA08 radium (223Ra) dichloride V10XX03

New ATC level codes (other than 5th levels): ACE inhibitors, other combinations C09BX Adrenergics in combination with anticholinergics R03AL 1

Change of ATC codes: Level name Previous ATC code New ATC code

fibrinogen, human B02BC10 B02BC30 2 ferric oxide polymaltose complexes B03AC01 B03AC 3 saccharated iron oxide B03AC02 B03AC 3 iron-sorbitol-citric acid complex B03AC03 B03AC 3 ferric sorbitol gluconic acid complex B03AC05 B03AC 3 ferric oxide dextran complexes B03AC06 B03AC 3 ferric sodium gluconate complex B03AC07 B03AC 3

Change of ATC code and/or ATC level name:

Previous New

R03AK03 fenoterol and other drugs R03AL01 fenoterol and ipatroprium bromide for obstructive airway diseases R03AK04 4 salbutamol and other R03AK04 salbutamol and sodium drugs for obstructive airway cromoglicate diseases R03AL02 salbutamol and ipatroprium bromide R03AK07 4 formoterol and other R03AK07 formoterol and budesonide drugs for obstructive airway R03AK08 formoterol and beclometasone diseases R03AK09 formoterol and mometasone

133 ATC/DDD Classification WHO Drug Information Vol. 27, No. 2, 2013

Change of ATC level names:

Previous New ATC code

Adrenergics and other drugs for Adrenergics in combination R03AK obstructive airway diseases with corticosteroids or other drugs, excl. anticholinergics reproterol and other drugs for reproterol and sodium R03AK05 obstructive airway diseases cromoglicate salmeterol and other drugs for salmeterol and fluticasone R03AK06 obstructive airway diseases Iron trivalent, parenteral preparations Iron, parenteral preparations B03AC thyrotropin thyrotropin alfa H01AB01

1 Split of ATC 4th level R03AK, separate 4th level for combinations with anticholinergics. 2 Combinations previously classified in B02BC10 should be altered to B02BC30 combinations (existing code). 3 ATC 5th levels deleted, all products classified on the 4th level only (B03AC Iron, parenteral preparations). 4 Separate ATC 5th levels for the various combinations (split of code). New ATC 4th level (R03AL) for combinations with anticholinergics.

New DDDs:

DDD unit Adm.R ATC code

aclidinium bromide* 0.644 mg Inhal powder R03BB05 gemigliptin 50 mg O A10BH06 colecalciferol 20 mcg O A11CC05 thyrotropin alfa 0.9 mg P H01AB01 pasireotide 1.2 mg P H01CB05 ivacaftor 0.3 g O R07AX02

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