WHO Drug Information 2015, vol. 29, 4 [full issue]

433 WHO Drug Information Vol. 29, No. 4, 2015 Contents Cooperation 435 CIOMS - A nongovernmental organization in official relations with WHO Pharmacopoeial standards 440 Ensuring the efficacy of a deworming medicine: albendazole chewable tablets Quality of medicines 446 The WHO CPP Scheme in today’s regulatory environment – is it time for change? Safety news 451 Restrictions Mirabegron: contraindicated in patients with severe hypertension; 451 Safety warnings Proton pump inhibitors: subacute cutaneous lupus erythematosus; Antiviral combinations for hepatitis C: liver injury; Daclatasvir hydrochloride and asunaprevir: interstitial pneumonia; Vemurafenib: potentiation of radiation toxicity ; Crizotinib: heart failure; Fingolimod: skin cancer ; Aripiprazole: impulse control disorders; Sodium polystyrene sulfonate: separate dosing to prevent interactions; Iodine-containing contrast agents: hypoactive thyroid in infants; 454 Known risks Magnesium oxide: hypermagnesaemia in older patients; Canagliflozin: decreased bone mineral density; Mycophenolate: avoid exposure in pregnancy; Ceftriaxone: acute generalised exanthematous pustulosis; Roxithromycin: pseudo–membranous colitis, cardiac effects ; Strontium: cardiovascular risks; Clozapine: severe neutropenia; Dimethyl fumarate and other fumarate- containing medicines: new monitoring measures ; 456 Unchanged recommendations Clopidogrel: no increased risk of death; Human papillomavirus vaccines: benefits outweigh risks; Entacapone: no clear evidence of cardiovascular events; 457 Removal of class warnings HIV medicines: class warnings about lipodystrophy and lactic acidosis removed 457 Safety reviews started 458 Packaging Improved packaging for dementia treatments; 458 Medicines quality Apotex: Canada import ban lifted, product re-testing imposed; Dibotermin alfa-containing implant kit: suspended in Europe; 459 Falsified product alert Falsified emergency contraceptive circulating in East Africa Regulatory news 460 Pre-market assessment Accelerated access pathways in Europe 460 Regulatory systems New Zealand working on new regulatory regime 460 Post-marketing control EMA initiative to improve patient registries 461 Collaboration and harmonization ICH announces organizational changes ; China and WHO collaborate on medicines quality; Meeting of World Pharmacopoeias held in China; Regulators of United Kingdom and India sign agreement; EMA and WHO share non-public information 463 Approved Insulin degludec & insulin aspart: for diabetes mellitus; Efmoroctocog alfa: for haemophilia A; Modified antihaemophilic factor (recombinant); Coagulation Factor X (human): for hereditary Factor X deficiency; Patiromer: for hyperkalaemia; Elvitegravir & cobicistat & emtricitabine & tenofovir alafenamide: for HIV infection; Uridine triacetate: for a rare hereditary metabolic disorder; Trifluridine & tipiracil: for advanced colorectal cancer; Blinatumomab: for certain acute lymphoblastic leukaemias; Necitumumab: for advanced squamous non-small cell lung cancer; Cobimetinib: for metastatic melanoma; Irinotecan liposome injection: for advanced pancreatic cancer; Carfilzomib: for a rare type of blood cancer; Ixazomib: for multiple myeloma; Talimogene laherparepvec: for advanced melanoma; Mepolizumab: for asthma; Osimertinib: for certain non-small cell lung cancers; Daratumumab: for multiple myeloma; Cariprazine: for schizophrenia and bipolar disorder; Pitolisant: for narcolepsy; Naloxone nasal spray: for opioid overdose; Idarucizumab: for reversal of dabigatran anticoagulant effect ; Patiromer: for hyperkalaemia; 468 EMA Article 58 positive opinion Pyronaridine-artesunate – paediatric antimalarial formulation 469 Extensions of indications Anthrax vaccine adsorbed: for post-exposure protection ; Ipilimumab: to prevent melanoma recurrence; Nivolumab: for renal cell cancer; Pembrolizumab: for advanced non-small cell lung cancer; 469 WHO endorsements Global Ebola virus and antibody reference standards; Malaria vaccine to be delivered in pilot projects Publications and events 471 Development Sustainable development goals aim at health for all 471 Access to medicines WHO publishes updated essential medicines lists; Medicines Patent Pool expands mandate to hepatitis C and tuberculosis; First patent pool licence for a hepatitis C medicine ; Controlled substances not accessible to all in need; Inefficiencies in the global insulin market Continued WHO Drug Information WHO Drug Information Vol. 29, No. 4, 2015 434 474 Health and trade European Council resolution defends public health interests; HAI/MSF report on EU trade policies and public health; WTO extends drug patent exemption for least-developed countries; New WHO publication about trade and health 475 Diseases Hepatitis world summit adopts Declaration; Malaria death rates plunge but risk remains; Tuberculosis remains a public health challenge ; Ebola still a public health emergency; Measles immunization gap persists 477 Antiretroviral treatment WHO recommends treatment for all people living with HIV ; Updated optimal list of ARVs for children 478 Antibiotics International summit on antibiotic resistance; Use of veterinary antibiotics in Europe; Multi-country survey reveals misconceptions on antibiotic resistance 479 Lists and manuals Indicators to assess pharmacovigilance systems; Specifications for selected HIV diagnostics 480 WHO matters WHO launches independent assessment of snake antivenoms; WHO Expert Committees on medicines meet in Geneva ; New web site on substandard and falsified medicines Consultation documents 482 The International Pharmacopoeia 482 Cycloserine 486 Cycloserine capsules 490 Ceftriaxone sodium 493 Ceftriaxone for injection ATC/DDD classification 496 ATC/DDD classification (temporary) 501 ATC/DDD classification (final) International Nonproprietary Names (INN) 503 Proposed INN: List 114 Continued Abbreviations and web sites CHMP Committee for Medicinal Products for Human Use (EMA) EMA European Medicines Agency (www.ema.europa.eu) EU European Union FDA U.S. Food and Drug Administration (www.fda.gov) Health Canada Federal department responsible for health product regulation in Canada (www.hc-sc.gc.ca) MHLW Ministry of Health, Labour and Welfare, Japan MHRA Medicines and Healthcare Products Regulatory Agency, United Kingdom (www.mhra.gov.uk) Medsafe New Zealand Medicines and Medical Devices Safety Authority (www.medsafe.govt.nz) PRAC Pharmacovigilance Risk Assessment Committee (EMA) PMDA Pharmaceuticals and Medical Devices Agency, Japan (www.pmda.go.jp/english/index.htm) Swissmedic Swiss Agency for Therapeutic Products (www.swissmedic.ch) TGA Therapeutic Goods Administration, Australia (www.tga.gov.au) U.S. United States of America Note: The online version of this issue (available at www.who.int/medicines/publications/druginformation) has direct clickable hyperlinks to the documents and web pages referenced. 435 WHO Drug Information Vol. 29, No. 4, 2015 Cooperation CIOMS - A nongovernmental organization in official relations with WHO The Council for International Organizations of Medical Sciences (CIOMS) aims to facilitate and promote international activities in the field of biomedical sciences, in collaboration with the United Nations (UN) and WHO. CIOMS has initiated and coordinated major long-term programmes around the topics of Health Policy, Ethics and Human Values - An International Dialogue and International Nomenclature of Diseases. Currently the main activities are within the areas of bioethics and drug development and use. Background The Council for International Organizations of Medical Sciences (CIOMS)1 was established by the World Health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949. Its offices are located in Geneva, close to WHO and the UN Palais des Nations. CIOMS has enjoyed excellent relations with both its “parents” since its creation and is in official relations with WHO and an associate partner of UNESCO. Through its membership, CIOMS is representative of the biomedical scientific community. The members of CIOMS include international and national professional associations, representing many of the biomedical disciplines, national academies of sciences and medical research councils (Annex 1). WHO is represented by at least one senior staff member in all CIOMS working groups. CIOMS also cooperates with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 1 www.cioms.ch (ICH) and the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). Activities In its more than six decades of existence, CIOMS has fostered a unique cooperation between specialized international medical associations and societies and other relevant stakeholders, and has promoted global activities in certain areas of the medical sciences whenever international cooperation is called for. CIOMS seeks to take into account the priorities, needs and resources of both industrialized and low-and-middle income countries (LMICs). As a nongovernmental organization, it is also able to draw on the considerable expertise existing in the research- based pharmaceutical industry where appropriate. Bioethics In the field of biomedical research involving human subjects, the World Medical Association (WMA) and CIOMS have been among the key international actors. In addition, the WHO input to Cooperation WHO Drug Information Vol. 29, No. 4, 2015 436 CIOMS activities in the field of research ethics is significant. A major output of this work have been the successive versions of the CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects (1). First issued in 1982 and revised in 1993 and 2002, these guidelines have been conceived to facilitate the practical implementation of the WMA’s Declaration of Helsinki (2) in WHO Member States, including low and middle income countries. A public consultation is ongoing for an update of these guidelines in line with recent developments, including the revision of the Declaration of Helsinki in 2013. The proposed revised text integrates the previous guidelines for biomedical research and those for epidemiological research (3) in one document. The draft text covers 25 distinct areas (Box 1), and is available for comments until 1st March 2016. This is a valuable opportunity for non-commercial research groups to provide their input. Box 1. Proposed updated CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects ►Available for public comment until 1st March 2016* Guideline 1 Social value Guideline 2 Research conducted in low-resource settings Guideline 3 Equitable distribution of benefits and burdens in the selection of groups of participants in research Guideline 4 Potential benefits and risks of research Guideline 5 Choice of control in clinical trials Guideline 6 Caring for participants’ health needs Guideline 7 Community engagement Guideline 8 Collaborative partnership and capacity building for research and review Guideline 9 Individual informed consent Guideline 10 Modifications and waivers of informed consent Guideline 11 Use of stored biological materials and related data Guideline 12 Use of health-related data in research Guideline 13 Reimbursement and compensation for research participants Guideline 14 Treatment and compensation for research-related harms Guideline 15 Research involving vulnerable persons Guideline 16 Research involving individuals who are not capable of giving informed consent Guideline 17 Research involving children and adolescents Guideline 18 Women as research participants Guideline 19 Pregnant women and lactating women as research participants Guideline 20 Research in disaster situations Guideline 21 Implementation research Guideline 22 Use of online information Guideline 23 Research ethics committees and review Guideline 24 Public accountability Guideline 25 Conflicts of interest * http://www.cioms.ch/index.php/guidelines-test 437 WHO Drug Information Vol. 29, No. 4, 2015 Cooperation Drug development and use CIOMS contributes significantly to the field of drug development and use. Its programme on drug development includes a series of working groups and other projects, which have addressed some fundamental topics and a wide range of issues centered around harmonizing the views of international systems and terminologies used for the safety surveillance of medicinal products and vaccines between stakeholders (Box 2). Some of the documents emanating from this work have served as a basis for ICH development and have led to the adoption of regulatory documents in WHO Member States. Given the aim of harmonization, it has been crucial to collaborate with all stakeholders. The independent status of CIOMS has permitted it to coordinate the contributions and expertise of senior scientists from research-based biopharmaceutical companies, national drug regulatory authorities, academia, and representative bodies of medical specialties to this harmonizing and strengthening of drug-safety surveillance measures. Scientists are invited to contribute based on their recognized specific expertise and, if required, in consultation with their background institution. Members and consulted experts and their affiliations are listed in the publications. CIOMS publications The consensus reports and documents discuss and recommend general principles and do not focus on individual medicinal products. As the CIOMS working groups have no legal jurisdiction or mandate to make binding decisions, reliance is placed on other bodies to incorporate the CIOMS recommendations, guidelines or good practices into a regulatory or legislative framework. Two publications created by CIOMS working groups are expected to be finalized in 2015: a publication by the CIOMS Working Group X on meta- analysis practices for clinical safety data, and an update of the report on Development and Rational Use of Standardised MedDRA® Queries (SMQs): Retrieving Adverse Drug Reactions with MedDRA (6). For 2016, a series of publications around vaccine safety and Box 2. Drug development and use: examples of CIOMS documents* • Management of drug safety data in the pre-and post-approval phases (4, 5) • Adverse drug reaction terminology and reporting (6) • International reporting of adverse drug reactions (CIOMS I reporting form**) • Pharmacogenetics (7) • Clinical pharmacology (8) • Pharmacovigilance in resource-limited countries (9) • Vaccine pharmacovigilance (10) • Practical aspects of signal detection in pharmacovigilance (11) • Practical approaches to risk minimization for medicinal products (12) * The CIOMS publications are available through the web sites of CIOMS and WHO (see footnotes on the next page) ** www.cioms.ch/index.php/cioms-form-i Cooperation WHO Drug Information Vol. 29, No. 4, 2015 438 communication is expected from a CIOMS Working Group on Vaccine Safety which was established in 2013 and is linked to WHO’s Global Vaccine Safety Initiative (GVSI). The findings and recommendations of groups convened under the auspices of CIOMS are widely disseminated. Many are available for ordering in printed form2, while others can be consulted online and in several cases downloaded without charge3. CIOMS publications can also be purchased directly from the CIOMS Secretariat, from WHO4, or from specialized bookshops. It should be emphasized that while the sole official versions of all CIOMS reports and guidelines are in English, several publications have been translated into other languages, generally at no cost to CIOMS. References 1 International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: Council for International Organizations of Medical Sciences (CIOMS), 2002. 2 World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053. 2 CIOMS Available Publications: http://www. cioms.ch/index.php/publications/available- publications/540/showCategory 3 CIOMS Printable Publications: http:// www.cioms.ch/index.php/publications/ printablev3/541/showCategory 4 WHO Bookshop. www.who.int/bookorders 3 International Ethical Guidelines on Epidemiological Studies. Geneva: Council for International Organizations of Medical Sciences (CIOMS), 2009. 4 Development Safety Update Report (DSUR) Harmonizing the Format and Content for Periodic Safety Report during Clinical Trials: Report of CIOMS Working Group VII. Geneva: Council for International Organizations ofCIOMS, 2006. 5 Management of Safety Information from Clinical Trials: Report of CIOMS Working Group VI. Geneva: CIOMS, 2005. 6 Development and Rational Use of Standardised MedDRA Queries (SMQs): Retrieving Adverse Drug Reactions with MedDRA. Geneva: CIOMS, 2004. 7 Pharmacogenetics : Towards improving treatment with medicines (Report of the CIOMS Working Group). Geneva: CIOMS, 2005. 8 WHO, IUPHAR, CIOMS. Clinical Pharmacology in Health Care, Teaching and Research. Geneva: CIOMS, 2012. 9 Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V. Geneva: CIOMS, 2013. 10 Definitions and Applications of Terms for Vaccine Pharmacovigilance. Geneva: CIOMS, 2012. 11 Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group VIII. Geneva: CIOMS, 2010. 12 Practical approaches to risk minimisation for medicinal products: Report of CIOMS Working Group IX. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS), 2014. 439 WHO Drug Information Vol. 29, No. 4, 2015 Cooperation Annex 1: CIOMS membership International members • World Allergy Organization • International College of Angiology • International Society of Audiology • International Union of Basic and Clinical Pharmacology (IUPHAR) • International Association of Bioethics • International Society of Internal Medicine • International Federation of Otorhinolaryngological Societies • World Association of Societies of Pathology and Laboratory Medicine (WASPaLM) • International Society for Pharmacoepidemiology (ISPE) • International Society of Pharmacovigilance (ISOP) • World Psychiatric Association • International Rhinologic Society • Medical Women’s International Association • World Medical Association National members • Comité des Académies Royales de Médecine, Belgium • Union of the Scientific Medical Societies of Bulgaria • Czech Medical Association, Czech Republic • Association of the Scientific Medical Societies in Germany • The Israel Academy of Sciences and Humanities, Israel • Korean Academy of Medical Sciences, Republic of Korea • Islamic Organization for Medical Sciences (IOMS), Kuwait • Royal Netherlands Academy of Arts and Sciences, Netherlands • The Research Council for Norway/ The National Committee for Medical Research Ethics, Norway • South African Medical Research Council, South Africa • Swiss Academy of Medical Sciences, Switzerland Associate members • Medical Sciences Society (MSS-UQ) of Queensland University, Haiti • American Society for Bioethics and Humanities • Consulta di Bioetica • World Federation of Chiropractic • International Federation of Clinical Chemistry and Laboratory Medicine • World Organization of Family Doctors (WONCA) • Good Clinical Practice - Alliance • International Council for Laboratory Animal Science (ICLAS) • International Society of Hepatic Encephalopathies & Nitrogen Metabolism (ISHEN) • Academy of Medical, Dental and Pharmaceutical Sciences of Japan • The World Association for Medical Law • International Union of Microbiological Societies • Asia Pacific Academy of Ophthalmology • International Union of Physiological Sciences • Federation of Polish Medical Organizations Abroad • Federation of Polish Medical Societies • International Medical Sciences Academy • National Fund for Scientific Research (NSFR) • International Federation of Medical Student Associations ►Source: http://www.cioms.ch/index. php/2012-06-07-19-16-08/membership æ 440 WHO Drug Information Vol. 29, No. 4, 2015 Pharmacopoeial standards Ensuring the efficacy of a deworming medicine: albendazole chewable tablets Parasitic infections affect more than a billion people worldwide, many of them children. Albendazole chewable tablets are an effective treatment and can be administered by non-medical staff such as parents and teachers. However, chewable tablets are sometimes swallowed whole, either intentionally or unintentionally. The International Pharmacopoeia therefore requires that chewable tablets – like conventional tablets – comply with the tests for disintegration and dissolution. The monograph included in The International Pharmacopoeia for albendazole chewable tablets was revised recently. It provides publicly available quality standards, including a new test for the dissolution of these widely used tablets. Ensuring pharmaceutical quality of essential medicines Pharmacopoeial standards help ensure the quality and safety of essential medicines by providing analytical methods and appropriate limits for testing and assessing the active pharmaceutical ingredients, excipients and finished products. The International Pharmacopoeia1 focuses on specifying the quality of essential medicines, i.e. those medicines that satisfy the health care needs of the majority of the population in WHO Member States. It underpins some of WHO’s most important activities, including those 1 Publicly available at: http://apps.who.int/phint/ en/p/about/ carried out by the WHO Prequalification Team: medicines and the Department of Control of Neglected Tropical Diseases, to assess and test the quality of medicines found in: • the WHO Model List of Essential Medicines and the WHO Model List of Essential Medicines for Children; • invitations to manufacturers to submit an expression of interest for product evaluation to the World Health Organization (WHO) Prequalification Team: medicines; and/or • other United Nations/WHO documents recommending the use of specific medicines for treating specific diseases and/or for use by treatment programmes. WHO provides The International Pharmacopoeia free of charge for WHO Member States to enable quality control testing of active ingredients and finished pharmaceutical products. An example of how these global specifications provide added value for WHO Member States was published in a previous edition of this journal*. In 2015, publication of the Fifth Edition of The International Pharmacopoeia (Ph. Int.) and the 50th annual meeting of the WHO Expert Committee which is mandated to keep it relevant and updated, represented two major landmarks. The paper presented here describes another example of a monograph, newly included in the Fifth Edition of Ph. Int., that contributes to bringing affordable, safe and efficacious medicines of good quality to everyone, everywhere. * Global specifications: the example of capreomycin. WHO Drug Information 2014; 28(4):431-3. 441 WHO Drug Information Vol. 29, No. 4, 2015 Pharmacopoeial standards Priority is placed on monograph development for essential medicines that are not included or not sufficiently described in other pharmacopoeias. Many of these medicines are needed urgently, either because current production does not cover global treatment needs or because available products are not quality-assured. Albendazole chewable tablets is one such medicine. Albendazole: a needed treatment Albendazole is an effective treatment for a range of parasitic diseases that represent a significant public health burden, as described below. Lymphatic filariasis Lymphatic filariasis, commonly known as elephantiasis, is a neglected tropical disease. It is caused by parasitic infection with nematodes (roundworms) of the family Filariodidea that are transmitted by mosquitoes. It is usually acquired in childhood and damages the lymphatic system. The painful and profoundly disfiguring visible manifestations of the disease occur later in life and lead to permanent disability. Patients are not only physically disabled, but suffer mental, social and financial losses contributing to stigma and poverty. Currently, 1.23 billion people in 58 countries live in areas where lymphatic filariasis is transmitted and are at risk of being infected. ► Lymphatic filariasis can be eliminated by stopping the spread of the infection through use of large-scale chemoprevention, consisting of a single dose of two medicines ― albendazole chewable tablets (400 mg) together with ivermectin tablets (150–200 µg/kg) or with diethylcarbamazine tablets (DEC) (6 mg/kg) ― given annually to an entire at-risk population. (1) Soil-transmitted helminth infections Soil-transmitted helminth infections are among the most common infections worldwide. They are transmitted by eggs present in human faeces which in turn contaminate soil especially in areas where sanitation is poor. The main species that infect people are the roundworm (Ascaris lumbricoides), the whipworm (Trichuris trichiura) and hookworms (Necator americanus and Ancylostoma duodenale). More than 1.5 billion people, or 24% of the world’s population, are infected with soil-transmitted helminth infections. Over 270 million preschool-age children and over 600 million school-age children live in areas with high transmission rates of these parasites and are in need of treatment and preventive interventions. ► The WHO recommended medicines – albendazole chewable tablets and mebendazole chewable tablets – are effective, inexpensive and easy to administer by non-medical personnel, for example teachers. (2) Chewable tablets: a question of definition Pharmacopoeias define chewable tablets differently. The definitions deviate from each other in particular with regard to administration (must be chewed or may be chewed) and, consequently, not all pharmacopoeias require a disintegration test (Box 1). In The International Pharmacopoeia, a disintegration requirement has been included to address concerns about the efficacy of chewable tablets that are swallowed whole, either intentionally or unintentionally. Pharmacopoeial standards WHO Drug Information Vol. 29, No. 4, 2015 442 The need for dissolution testing Monographs for solid oral dosage forms in The International Pharmacopoeia usually contain a dissolution test and/ or a disintegration test. The choice of testing disintegration or dissolution for a given product is based on international standards such as the International Council for Harmonisation (ICH) guideline on Test Procedures and Acceptance Criteria for New Drug Products (3). This guideline advises that disintegration testing may be sufficient for rapidly dissolving medicines containing active ingredients that are highly soluble in the body. For albendazole chewable tablets, Box 1. Definition of chewable tablets and disintegration requirements in different pharmacopoeias • The European Pharmacopoeia (Ph. Eur. 8.7) states in the general monograph on tablets that “Chewable tablets are intended to be chewed before being swallowed.” As chewable tablets are not exempted from the test for disintegration of uncoated (or coated) tablets, they are required to comply with the test for disintegration. • The British Pharmacopoeia (2016) includes the general monograph on tablets of the European Pharmacopoeia and would thus require that (uncoated or coated) chewable tablets comply with the test for disintegration. However, the requirement for disintegration usually does not apply either because the individual monographs on chewable tablets explicitly mention this or because a requirement for dissolution eliminates the need for a disintegration test (see also chapter entitled “Tablets” of the British Pharmacopoeia). • The United States Pharmacopeia (USP 38) states (in the section on tablets that is included in the general chapter on Pharmaceutical Dosage Forms <1151>) that “tablets […] that include ‘chewable’ in the title must be chewed or crushed prior to swallowing to ensure reliable release of the drug substance(s) or to facilitate swallowing. If tablets are designed so that they may be chewed (but chewing is not required for drug substance release or ease of swallowing), the title should not include a reference to ‘chewable’.” Following this definition, chewable tablets are exempted from the disintegration test: “Chewable tablets are not required to comply with the disintegration test” (section on chewable tablets in the general chapter: <2> Oral Drug Products – Product Quality Tests). • The general chapter on tablets in the Indian Pharmacopoeia (2014) determines that the disintegration requirement for uncoated and coated tablets does not apply to chewable tablets. In the section on “Tablets for Use in the Mouth” it is stated that “where applicable the tablets should be chewed before swallowing”. • The Chinese Pharmacopoeia (2010) specifies that “chewable tablets are tablets intended to be chewed and then swallowed” and that “chewable tablets may not be required to comply with the test for disintegration.” (Appendix I, General Requirements for Preparations). • According to The International Pharmacopoeia (Fifth Edition), chewable tablets are usually uncoated, and as such they have to disintegrate within 15 minutes (see general monograph on Tablets). This requirement was included to address concerns about the efficacy of chewable tablets that are swallowed whole. This may occur either intentionally or unintentionally. Accordingly, The International Pharmacopoeia defines chewable tablets as tablets that “are intended to be chewed before being swallowed; however, where indicated on the label, they may be swallowed whole instead”. 443 WHO Drug Information Vol. 29, No. 4, 2015 Pharmacopoeial standards however, disintegration testing cannot replace dissolution testing as the solubility of albendazole at 37°C throughout the physiological pH range (pH value 1–7.5) is reported to be low (4, 5). Compendial dissolution tests provide information about the drug-release characteristics of a particular formulation, or batch of a product, under standardized test conditions. Compliance with a dissolution test provides assurance that most of the active ingredient will dissolve in an aqueous medium within a reasonable amount of time when the preparation is subject to mild agitation. However, compliance with a dissolution test does not in itself guarantee bioavailability. Failure to comply with a dissolution test, on the other hand, may indicate that the bioavailability of the product is too low, since the active substance must be released from the dosage form for any local or systemic pharmacological activity to occur. Surveys have shown that the dissolution properties of albendazole chewable tablets on the market are poor. In 2011 a survey of medicines for neglected tropical diseases showed that 57% of the products tested failed to comply with dissolution test requirements (6). A more recent study, performed in Ethiopia, produced similar results, with 8 of 19 tested albendazole tablets (42%) failing to comply with the dissolution test (7). Investigations suggest that albendazole chewable tablets that pass disintegration and in vitro dissolution tests have better clinical effects, measured as cure rates and egg reduction rates for Ascaris lumbricoides, Trichuris trichiura and hook- worm infections, than those that fail these tests (8). Although the clinical implications of failure to comply with dissolution test requirements need to be evaluated in detail, it is very likely that the efficacy of albendazole tablets is compromised if the ingredients are not released from the tablets. A publicly available test method to verify the dissolution properties of albendazole chewable tablets is therefore urgently needed. Setting up the dissolution requirements Most guidance documents on dissolution testing require that chewable tablets – the whole tablets, not the crushed tablets – are subjected to in vitro dissolution testing (9). The FIP/AAPS guidelines (10) state: “In principle, the test procedure employed for chewable tablets should be the same as that for regular tablets. This concept is based on the possibility that a patient might swallow the dosage form without proper chewing, in which case the drug will still need to be released to ensure the desired pharmacological action.” However, “because of the non- disintegrating nature of the dosage form, there may be a necessity to alter test conditions (e.g. increase the agitation rate) and specifications (e.g. increase the test duration).” To elaborate a dissolution test for albendazole chewable tablets for inclusion in The International Pharmacopoeia samples of albendazole chewable tablets were investigated for their in vitro release of the active ingredient. The product chosen for this investigation was the comparator product recommended for bioequivalence testing of medicines undergoing WHO prequalification (11), since that product’s quality, safety and efficacy have been fully assessed and documented in premarketing studies and post-marketing monitoring schemes. The comparator product can be swallowed whole, or crushed or chewed Pharmacopoeial standards WHO Drug Information Vol. 29, No. 4, 2015 444 and swallowed with water. Existing pharmacopoeial dissolution test conditions for albendazole tablets were taken as a starting point for the WHO investigations. The volume and composition of the dissolution medium were retained; but a higher rotation speed was selected to compensate for the non-disintegrating character of the dosage form. The final test conditions (Box 2) were found to be discriminative, meaning that the modified test is suitable for comparing and evaluating the in vitro release properties of albendazole chewable tablets on the market. Adoption process The procedure for developing monographs for The International Pharmacopoeia (12) is designed to ensure wide consultation and transparency, providing stakeholders and interested parties with the opportunity to submit comments on draft documents. The draft revision of the monograph on albendazole chewable tablets, including the new dissolution test, was therefore sent out for public consultation in June 2014 and posted on the WHO website (13) with an invitation to provide comments. Thereafter it was submitted, together with a compilation of all comments received, to the Expert Committee on Specifications for Pharmaceutical Products in October 2014. The Committee carefully reviewed the comments and adopted the revised monograph, including the new dissolution test (14). The revised monograph on albendazole chewable tablets is available in the Fifth Edition of The International Pharmacopoeia (15). References 1 WHO Media Centre. Lymphatic filariasis. Fact sheet N° 102.Updated May 2015 [web page]. 2 WHO Media Centre. Soil-transmitted helminth infections. Fact sheet N° 366. Updated May 2015 [web page]. 3 ICH Harmonised Tripartite Guideline. Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: Chemical substances. Q6A. Step 4 version. ICH: 1999. Box 2. The International Pharmacopoeia*: Dissolution test requirements for albendazole chewable tablets Carry out the test as described under Section 5.5 Dissolution test for solid oral dosage forms using 900 mL of hydrochloric acid (~3.65 g/L) TS as the dissolution medium and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw a sample of about 15 mL of the dissolution medium through an in-line filter. Cool the filtered sample to room temperature. Transfer 1.0 mL of the clear filtrate to a 50 mL volumetric flask and dilute to volume with sodium hydroxide (0.1 mol/L) VS. Measure the absorbance (1.6) of a 1 cm layer of the resulting solution at the maximum at about 308 nm, using sodium hydroxide (0.1 mol/L) VS as the blank. For each of the six tablets tested calculate the total amount of albendazole (C12H15N3O2S) in the medium using the absorptivity value of 74.2 ( = 742). The amount in solution for each tablet is not less than 80% (Q) of the amount declared on the label. * The International Pharmacopoeia is available on CD and online at http://apps.who.int/phint/en/p/about/ 445 WHO Drug Information Vol. 29, No. 4, 2015 Pharmacopoeial standards 4 Lindenberg, M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004 Sep;58(2):265-78. 5 WHO. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Annex 8. In: WHO Technical Report Series, No. 937. Geneva, Switzerland: 2006 6 Chewable tablets: time to reassess a “neglected” dosage form? WHO Drug Information 2011;25(3):223-7. 7 Suleman S, Zeleke G, Deti H et al. Quality of Medicines Commonly Used in the Treatment of Soil Transmitted Helminths and Giardia in Ethiopia: A Nationwide Survey. PLoS Negl Trop Dis. 2014 Dec; 8(12): e3345. doi: 10.1371/journal. pntd.0003345. 8 Albonico M, Mathema P, Montresor A et al. Comparative study of the quality and efficacy of originator and generic albendazole for mass treatment of soil- transmitted nematode infections in Nepal. Trans R Soc Trop Med Hyg. 2007 May;101(5):454-60. Epub 2006 Nov 28. 9 U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. Revision 1, March 2003. 10 Brown CK, Friedel HD, Barker AR et al. FIP/ AAPS Joint Workshop Report: Dissolution/ In Vitro Release Testing of Novel/Special Dosage Forms. Indian J Pharm Sci. 2011 May-Jun; 73(3): 338–53. 11 WHO Prequalification of Medicines Programme. Recommended comparator products: Neglected Tropical Diseases. Guidance Document, 25 August 2015. 12 WHO. Procedure for the development of monographs and other texts for The International Pharmacopoeia. Annex 1. In: WHO Technical Report Series, No. 992. Geneva, Switzerland: 2015. 13 WHO. Essential medicines and health products. Current projects [web page]. www.who.int/medicines/areas/quality_ safety/quality_assurance/projects/en/ 14 WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty- ninth Report. WHO Technical Report Series, No. 992. Geneva, Switzerland: 2015. 15 WHO. The International Pharmacopoeia. Fifth Edition. Geneva, Switzerland: 2015. Available free of charge at: http://apps.who.int/phint/en/p/about/ æ 446 WHO Drug Information Vol. 29, No. 4, 2015 Quality of medicines The WHO CPP Scheme in today’s regulatory environment – is it time for change? Is the fundamental purpose of providing a Certificate of Pharmaceutical Product (CPP) to assist worldwide patient access to novel medicines still true today? Background The WHO Certification Scheme for Certificates of Pharmaceutical Products (CPP) is an international voluntary agreement to provide assurance to countries participating in the Scheme about the quality of pharmaceutical products moving in international commerce. The Scheme was originally endorsed in 1969 as a powerful instrument to assist national regulatory authorities in sharing information and avoiding duplication. This key principle still holds true. However, since 1997 the Scheme has not changed despite dramatic changes in the regulatory environment within both the issuing and recipient CPP markets. In this article we examine the Scheme as it is used today and ask: is it time for change? The CPP Network of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) has been collecting experience of how the Scheme operates and influences patient access to medicines. The key observations and recommendations of the Network are described in this article. The WHO Certification Scheme was originally endorsed by the World Health Assembly in 1969 and has been revised several times, with each revision being endorsed by the World Health Assembly. To enable the continued adaptation of Scheme’s use in a rapidly changing environment without the need for intervention by the World Health Assembly, a Questions and Answers (Q & A) document was prepared in 2010 and published as a working document1. In 2014 the Expert Committee on Specifications for Pharmaceutical Preparations recommended that the Q & A document should be updated. The CPP Network team of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) proposed a revised document, which was adopted by the Committee in October 2015 based on the usual public consultation process2 and is planned to be published in the next issue of WHO Drug Information. The article shown below reflects the thoughts of the IFPMA CPP Network team about the current use of the CPP Scheme. 1 WHO Certification Scheme: questions and answers. WHO Drug Information 2011; 25(2):113-121. (Also available as: Working Document QAS 10.374, May 2010.) 2 WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce: Questions and answers (Q & A). Proposal for revision. Working document QAS/15.623, June 2015. We thank Marianne Vogt, Heather Hockenhull and the members of the IFPMA CPP Network for their work on the revision of the CPP Questions and Answers document, and for contributing this article. 447 WHO Drug Information Vol. 29, No. 4, 2015 Quality of medicines Not all accredited authorities meet the requirements or template stated in the guidelines for the Scheme when CPPs are issued. More than 130 countries are member states of the Scheme or acknowledge and accept the Scheme. However, not all the authorities meet the requirements or adhere to the WHO template guidelines. This is problematic and often leads to confusion within the recipient countries when the requirements and template vary dependent on the issuing health authority (HA). This can be avoided if the template guidance is adhered to. To address this issue, we recommend that all issuing HAs use the WHO template, which will also lead to improvements in legalization requests. When the guidance is followed, many recipient HAs do not request additional certification of the CPP. The way to apply for a CPP is not harmonized, with each certifying authority having its own system. There are a variety of systems and procedures across issuing countries on how to apply for a CPP. In order to achieve more transparency of these processes and lead times, it would be helpful to work towards regional harmonization and a standard electronic submission. Harmonization of CPP applications and of payment approaches or methods should be realistic goals resulting in consistent timelines and efficient planning. Some certifying authorities have different interpretations of the CPP Scheme, limiting the issuance of a CPP to products manufactured and exported from the certifying country only. Due to differing interpretation of the Scheme across issuing HAs, when a product is not manufactured in and exported from the issuing HA country, a full CPP may not be issued and sometimes no CPP will be issued at all. This can result in a substantial delay in registration and patient access within CPP-dependent markets. In line with the original concept of the WHO Scheme a CPP can be issued as soon as the product is approved, independently of where it is manufactured, released and exported from. Adherence to this principle will then allow for products to be registered within shorter time frames in the recipient markets, allowing patients to access the medicines earlier. The good manufacturing practice (GMP) status given in the CPP is not recognized by recipient countries. A key principle of the Scheme is to share information and avoid duplication. In this important aspect, an additional aim of the Scheme is to certify that the respective facilities and operations conform to GMP as recommended by WHO. WHO clearly discourages the request of a separate GMP certificate since the GMP statement included in the CPP should be acceptable. Quality of medicines WHO Drug Information Vol. 29, No. 4, 2015 448 There are inconsistencies in listing the trade name of the product in the recipient country, if different from the certifying country. Generally most of the certifying countries allow the trade name of the recipient country on the CPP. However, in some cases the trade name is not part of the formatted template application and therefore cannot be displayed within the CPP. Thus HAs can have difficulty recognizing that the CPP prepared by the issuing country is for the same product as that being registered, renewed or varied within the recipient country. The recommendation is that all issuing HAs have the option to include the trade name of the recipient country within the CPP. There is lack of understanding that the CPP reflects the approval status of the certifying country only. For CPP-dependent markets the CPP is classified as the key document for a successful submission and eventually approval of a drug product. The content of the CPP is extremely important to the recipient market – in most cases the recipient HA requires that the drug product they will receive mirrors exactly the drug product that has been approved by the certifying HA. However, complexities in modern global sourcing routes do not always allow for a direct match. When various steps of the manufacturing process differ between the recipient and issuing countries, this may result in queries and can cause unnecessary delays in approval. We recommend awareness and educational initiatives to clarify to the recipient HAs that the CPP reflects the approval status in the issuing country only with the information on the basis of which it has been approved. The CPP is no longer provided to substitute the full dossier quality safety and efficacy (QSE) review. Today many countries require provision of the CPP in addition to carrying out their own QSE review thus increasing the time for approval and patient access to novel medicines. In recent years we have seen rapid changes to the global regulatory landscape; however, in many countries the use of the WHO Certification Scheme has remained largely unchanged for the last 20 years. More countries than ever before receive full dossiers, including the country-specific Module 1 of the Common Technical Document (CTD) containing all the details provided in the CPP, from GMP certificates to worldwide marketing authorization (MA) status. In order to reaffirm the original intention of the CPP i.e. to support countries with “limited drug regulatory capacity”, countries capable of carrying out a full QSE evaluation should be advised to review their regulatory requirements and cease to require a CPP as a mandatory element for approval, unless it is to be used for a priority review thus accelerating patient access to novel medicines. CPPs are required in the majority of reference country approval markets as a prerequisite for a regulatory submission rather than being provided just prior to approval. CPPs are mostly required as a prerequisite for applications in the full life cycle of the drug product (from MA approval to subsequent renewals and variations), thereby directly impacting the availability of novel drugs for patients in those markets. Furthermore, authorities in these markets are moving from requesting an abbreviated dossier (by 449 WHO Drug Information Vol. 29, No. 4, 2015 Quality of medicines relying on approval in a reference market) to a more complex regulatory framework which includes a full dossier (e.g. ICH CTD) plus the CPP. This situation leads to excessively lengthy submission and approval timelines. It is recommended that HAs accept abbreviated dossiers when they are requesting CPPs and that CPPs are not a requirement for the initial review cycle but can be provided at a later time. Required consulate/embassy legalizations lead to delays in CPP availability. The CPP is a legal document that adheres to the principles of WHO which are endorsed by the majority of countries. Consulate legalization is sometimes required, which is beyond the international rules for the exchange of certificates and documents as it does not provide any enhanced evidence of authenticity and does not provide value to the safety of the patients. In addition, required legalizations lead to delays in CPP availability, impacting registration timelines and the availability of new medicines to patients. Where a country requires a CPP prior to the approval of a product, consulate/ embassy legalization should not be required since the CPP was issued by the HA in accordance with the adopted WHO requirements. Lead times of the certifying authorities can be very long, sometimes several months. Experience shows that there are differences in the timelines for issuing of CPPs across national authorities, ranging from days to several months. Lengthy issuing times from certifying authorities, especially those from source countries of new medicines, increase registration timelines and delay availability of those medicines in CPP-dependent markets. It is recommended that HAs that have successfully implemented shorter issuing timelines share best practices with others where issuing timelines are longer. In addition, there are no specific review timelines for CPP requests. If there is an issue with the application, the applicant is not informed until many weeks after the initial application. Opportunity for the applicant to discuss the submission with the issuing HA during the process would benefit both the HA and the applicant and allow for any corrections or updates to be managed efficiently. The marketing authorization holder (MAH) stated within the CPP can be registered as the MAH within the recipient country license. There has been a growing trend within markets requiring reference country approval to register the MAH listed within the CPP as the MAH within the recipient market. This leads to issues as the MAH can differ depending on the issuing HA’s legislative requirements. In addition there is often a requirement within the recipient HA, that the MAH must be from where the product is formulated and/or released. This makes it impossible to provide a CPP that fits the legislative requirements in the recipient country. Is it correct to use the CPP content in this way? This is not aligned with the Scheme’s original purpose to ensure QSE of the drug product moving in international commerce, regardless of whether the MAH listed in the CPP formulates and/or releases the drug product. The original purpose of the Scheme should be reflected within the Quality of medicines WHO Drug Information Vol. 29, No. 4, 2015 450 recipient HA legislative requirements, allowing CPPs to be provided to support regulatory submissions with proof of the QSE of the drug product only. Conclusion In answer to the question, “Is the fundamental purpose of providing a CPP to assist worldwide patient access to novel medicines still true today?” we have the following opinion: The CPP Scheme is still valid, but not in its current state and only when used to support countries that do not have the infrastructure to complete a full dossier quality, safety and efficacy review themselves. For the Scheme to be successful now and in the future, both recipient and issuing HAs need to work together with WHO and the pharmaceutical industry to harmonize CPP templates, align legislative requirements of recipient countries, reduce timelines and accept the CPP at a later time within the review cycle. Whilst doing this we also need to remain focused on the initial fundamental purpose of the Scheme, ensuring its continuous improvement and adaptation as we move forward with advancements within the regulatory environment. Only once this has been achieved, will the Scheme work again to its full potential, positively impacting patients worldwide independent of their regulatory authorities’ resources and capability. æ WHO Drug Information Vol. 29, No. 4, 2015 451 Safety news Restrictions Mirabegron: contraindicated in patients with severe hypertension; U n i t e d K i n g d o m – The marketing authorization holder, in consultation with the MHRA, has informed health professionals of cases of severe hypertension reported in patients taking mirabegron (Betmiga®), including hypertensive crisis associated with cerebrovascular and cardiac events (mainly transient ischaemia attack or stroke). Mirabegron is now contraindicated in patients with severe uncontrolled hypertension with a systolic blood pressure of 180 mm Hg or higher and/ or a diastolic blood pressure of 110 mm Hg or higher. Blood pressure should be measured before starting treatment and periodically during treatment, especially in patients with hypertension. Mirabegron is used in the management of urinary frequency, urgency, and incontinence in overactive bladder syndrome. It is known that mirabegron can increase blood pressure. Health professionals were also reminded of restrictions in the use of mirabegron in patients with renal impairment and in those with hepatic impairment who are also taking strong inhibitors of cytochrome P450 3A such as itraconazole, ketoconazole, ritonavir, or clarithromycin, as this will lead to increased exposure (area under the curve, AUC) of mirabegron. ►MHRA. Drug Safety Update vol 9 issue 3 October 2015: 1. Safety warnings Proton pump inhibitors: subacute cutaneous lupus erythematosus U n i t e d K i n g d o m – The MHRA has warned that proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematosus (SCLE), especially in sun-exposed areas of the skin. Health professionals should suspect SCLE in patients treated with a proton pump inhibitor who develop such lesions and who report arthralgia. Treatment discontinuation should be considered unless it is imperative for a serious acid-related condition. In most cases, symptoms resolve on PPI withdrawal. If there are no signs of remission after a few weeks or months, treatment with topical or systemic steroids may be necessary. ►Drug Safety Update vol 9 issue 2 September 2015: 1. Antiviral combinations for hepatitis C: liver injury U n i t e d S t a t e s o f A m e r i c a – The FDA has warned about the risk of potentially serious liver injury in patients taking one of two antiviral fixed-dose combination products used to treat chronic hepatitis C: dasabuvir, ombitasvir, paritaprevir, and ritonavir (Viekira Pak®) and ombitasvir, paritaprevir, and ritonavir (Technivie®). Information about this safety risk has been added to the product information for the two medicines. Technivie® is FDA-approved for use in patients with genotype 4 chronic hepatitis Safety news WHO Drug Information Vol. 29, No. 4, 2015 452 C virus infection without cirrhosis, while Viekira Pak® is FDA-approved for use in patients with genotype 1 chronic hepatitis C infection including those with compensated cirrhosis. Serious outcomes were reported mostly in patients taking Viekira Pak® who had evidence of advanced cirrhosis before starting treatment with the drug. (1) C a n a d a – In response to new international safety information about serious cases of liver injury, Health Canada has recommended updates to product information for the fixed-dose combination of ombitasvir/paritaprevir/ ritonavir and dasabuvir (Holkira Pak®) and the fixed-dose combination of ombitasvir/ paritaprevir/ritonavir (Technivie®). (2) ► (1) FDA Drug safety communication, 22 October 2015. (2) Health Canada Advisory, 10 November 2015. Daclatasvir hydrochloride and asunaprevir: interstitial pneumonia J a p a n – The PMDA has requested that product information for daclatasvir hydrochloride (Daklinza®) and asunaprevir (Sunvepra®) should be updated to include information about the risk of interstitial pneumonia in patients treated with a combination of the two medicines. This follows 11 cases reported in Japan in the last three years, including four where causality could not be ruled out. ►PMDA Summary of investigation results and Revision of Precautions, 20 October 2015. Vemurafenib: potentiation of radiation toxicity U n i t e d K i n g d o m – The MHRA has alerted prescribers to the risk of potentiation of radiation toxicity in patients treated with radiation before, during, or following treatment with vemurafenib (Zelboraf®). Vemurafenib should be used with caution in such patients. The risk was identified in a review of worldwide data by EU medicines regulators. Severe cases of radiation- related injuries, including some with fatal outcome, have been reported. In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day. The events included radiation recall and radiation sensitization. Most cases were cutaneous in nature but some cases involved visceral organs. ►Drug Safety Update Vol 9 issue 4, November 2015: 2. Crizotinib: heart failure U n i t e d K i n g d o m – The MHRA has warned health professionals about the risk of severe and potentially fatal cardiac failure in patients treated with crizotinib (Xalkori®) identified in a review by European medicines regulators. Health professionals should monitor all patients for signs and symptoms of heart failure, including dyspnoea, oedema, or rapid weight gain from fluid retention. A dose reduction, treatment interruption or treatment discontinuation should be considered if any of these symptoms occur. ►Drug Safety Update vol 9 issue 3, November 2015: 1. 453 WHO Drug Information Vol. 29, No. 4, 2015 Safety news Fingolimod: skin cancer C a n a d a – Health Canada has approved updates to the product information for the multiple sclerosis drug fingolimod (Gilenya®) to warn about two specific risks associated with the medicine’s action on the immune system. A Health Canada safety review found that fingolimod may increase the risk of cancers, particularly of the skin. Patients and health professionals should be vigilant for symptoms of skin cancer. Information on the risk of progressive multifocal leukoencephalopathy (PML), as reported in the EU and the U.S. earlier this year, was also added. The risk of lymphoma and of infections was already mentioned in the Canadian monograph. ►Health Canada Advisory, 30 September 2015. Aripiprazole: impulse control disorders C a n a d a – Health Canada has approved updates to the product information of aripiprazole (Abilify®) to include a warning about an increased risk of impulsive behaviours of pathological gambling and hypersexuality. (1) Aripiprazole tablets are authorized to treat a serious type of bipolar disorder, schizophrenia and related severe psychotic disorders and major depressive disorder in adults when used in combination with other drugs. The solution for injection is used for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or in patients with manic episodes in Bipolar I Disorder, when oral therapy is not appropriate. A long-acting product (Aristada®, Abilify Maintena®) – a prolonged-release suspension for injection – is used for maintenance treatment of schizophrenia in adults. ► (1) Health Canada Advisory, 2 November 2015. Sodium polystyrene sulfonate: separate dosing to prevent interactions U n i t e d S t a t e s o f A m e r i c a – The FDA has informed health professionals that additional studies are being required for the potassium-lowering medicine sodium polystyrene sulfonate (Kayexalate® and generic brands), to investigate its possible interaction with other drugs. Similarly to the recently licenced drug patiromer (Veltassa®), sodium polystyrene sulfonate might bind to other medications, potentially decreasing their effects. To reduce this potential risk, prescribers and patients should consider separating dosing of sodium polystyrene sulfate from that of any other oral medications – both prescription and non-prescription drugs – by at least six hours. Health care professionals should monitor blood levels or clinical response to the other medications when appropriate. ►FDA Drug safety communication, 22 October 2015. Iodine-containing contrast agents: hypoactive thyroid in infants; U n i t e d S t a t e s o f A m e r i c a – The FDA has advised that rare cases of underactive thyroid have been reported in infants younger than 4 months following the use of contrast media containing iodine for X-rays and other medical imaging procedures. In all of the reported cases, the infants were either premature or had other serious underlying medical conditions. Available evidence suggests Safety news WHO Drug Information Vol. 29, No. 4, 2015 454 that this is a rare effect that usually resolves without treatment or lasting effects. Manufacturers of affected products have been required to conduct a study to investigate this safety issue further. Product information for all iodinated contrast media is being updated to include information about these cases. The FDA will continue to evaluate this issue. ►FDA Drug safety communication, 17 November 2015. Known risks Magnesium oxide: hypermagnesaemia in older patients J a p a n – The PMDA has warned that numerous cases of hypermagnesaemia have been reported in geriatric patients treated with magnesium oxide granules or tablets, with some serious outcomes even if the renal function was normal or if the dosage was below the recommended dose. In many cases, the hypermagnesaemia was only detected when serious outcomes such as loss of consciousness occurred. Product information has been updated with advice that the medicine should be used with caution in geriatrics. Patients should be instructed to stop taking the medication and seek medical help immediately if they experience vomiting, bradycardia, muscular weakness, or somnolence. Patients should be carefully monitored with periodic measurement of serum magnesium concentration. For over-the-counter laxatives containing magnesium oxide, advice has been added to the package insert that elderly persons should consult a health professional before taking the product. ►PMDA Summary of investigation results and Revisions of precautions for prescription products, 20 October 2015. PMDA Summary of investigation results and Revisions of precautions for over-the- counter laxatives, 20 October 2015 Canagliflozin: decreased bone mineral density U n i t e d S t a t e s o f A m e r i c a – Based on updated information from several clinical trials the FDA has strengthened its warning about the increased risk of bone fractures in patients treated with the antidiabetic medicine canagliflozin (Invokana®, Invokamet®). Fractures can occur as early as 12 weeks after starting the drug. New information about the risk of decreased bone mineral density has been added to the section on adverse reactions in the product information. Health care professionals should consider factors that contribute to fracture risk before starting patients on canagliflozin. The FDA is evaluating the risk of fractures with other SGLT2 inhibitors registered in the U.S., including dapagliflozin (Farxiga®, Xigduo XR®) and empagliflozin (Jardiance®, Glyxambi®, Synjardy®). ►FDA Drug safety announcement, 10 September 2015. Mycophenolate: avoid exposure in pregnancy E u r o p e a n U n i o n – The EMA has strengthened its warnings about exposure of pregnant women to the transplant medicine mycophenolate (CellCept® and other brand names) either by treatment with the medicine or through unprotected sex with a man taking the medicine. A 455 WHO Drug Information Vol. 29, No. 4, 2015 Safety news routine re-assessment of the benefits and safety of mycophenolate has provided updated evidence on the significant risk of birth defects and spontaneous abortions. Pregnant women should only be exposed to mycophenolate if there is no suitable alternative to prevent transplant rejection. Mycophenolate can persist in blood for six weeks after treatment, and in sperm for 90 days after treatment. Updated product information will emphasize the need for contraception with two effective methods during and after treatment, pregnancy testing as appropriate, and the need to avoid donating blood or sperm during and after treatment with mycophenolate. ►EMA Press release, 23 October 2015. Ceftriaxone: acute generalised exanthematous pustulosis J a p a n – The PMDA has requested updates to the product information to ceftriaxone sodium hydrate to include the risk of acute generalised exanthematous pustulosis. This follows reports of this adverse event in patients treated with ceftriaxone sodium hydrate both in Japan and overseas. A warning about this risk is included in the product information for ceftriaxone-containing medicines approved in the European Union. ►PMDA Summary of investigation results and Revisions of precautions, 20 October 2015. Roxithromycin: pseudo– membranous colitis, cardiac effects J a p a n – The PMDA has required updates to the product information for roxithromycin-containing medicines to warn about the risks of pseudomembranous colitis and of QT interval prolongation and ventricular tachycardia, including torsade de pointes. This follows reports of these events in Japan and elsewhere. Approved product information in the European Union includes warnings about these effects. ►PMDA Summary of investigation results and Revision of precautions, 20 October 2015. Strontium: cardiovascular risks C a n a d a – Health Canada has implemented strengthened warnings on cardiovascular risks associated with products containing strontium citrate, strontium gluconate or strontium lactate with a daily dose of strontium between 4 mg and 682 mg, which are used to help support bone mineral density. These products are now limited to users who have no history of heart disease, circulatory problems or blood clots, or risk factors for these conditions. A healthcare professional should be consulted if the product is used longer than six months. This follows a Health Canada review undertaken in light of findings in Europe that led to restrictions for strontium ranelate at strontium doses of 680 mg/ day. A Health Canada review of strontium ranelate at daily doses below 680 mg/ and of non-ranelate forms of strontium did not lead to firm conclusions. However, Health Canada is using a precautionary approach and considers that strontium- containing medicines may potentially have cardiovascular side effects in people who are already at risk. ►Health Canada advisory, 22 October 2015. Clozapine: severe neutropenia U n i t e d S t a t e s o f A m e r i c a – The FDA has approved changes to the requirements for monitoring, prescribing, dispensing and receiving Safety news WHO Drug Information Vol. 29, No. 4, 2015 456 the schizophrenia medicine clozapine, to address continuing safety concerns about severe neutropenia. A new, shared risk evaluation and mitigation strategy (REMS), the so-called Clozapine REMS Program, replaces the separate clozapine registries maintained by individual manufacturers. In addition, neutropenia should now be monitored by the absolute neutrophil count (ANC) only, rather than in conjunction with the white blood cell count. Patients with benign ethnic neutropenia (BEN) are now also eligible for clozapine treatment. The ANC below which treatment should be interrupted in case of suspected clozapine-induced neutropenia has been lowered to 1 000 cells/mm3, and to 500 cells/mm3 for patients with BEN. ►FDA Drug safety communication, 15 September 2015. Dimethyl fumarate and other fumarate-containing medicines: new monitoring measures ; E u r o p e a n U n i o n –The EMA has issued advice in order to minimize the risk of progressive multifocal leukoencephalopathy (PML) in patients treated with the multiple sclerosis medicine dimethyl fumarate (Tecfidera®). This follows reports of PML in patients that were not treated with any other medicines that may increase the risk of PML. According to the new recommendations a complete blood count should be performed before starting treatment and every three months thereafter. Additionally, a baseline MRI should be provided. If during treatment the treatment lymphocyte counts drop to very low levels for more than six months, health professionals should consider stopping treatment. If treatment is continued, patients should be closely monitored. Related recommendations have been issued for two fumarate-containing medicines used to treat psoriasis (Fumaderm® and Psorinovo®). ►EMA Press release, 23 October 2015. Unchanged recommendations Clopidogrel: no increased risk of death U n i t e d S t a t e s o f A m e r i c a – The FDA has determined that long-term use of the antiplatelet drug clopidogrel (Plavix®) does not increase or decrease overall risk of death in patients with, or at risk for, heart disease. Neither did a review of clinical trials suggest that clopidogrel increases the risk of cancer or death from cancer. The FDA’s recommendations remain unchanged. Health care professionals should consider the benefits and risks of available antiplatelet medicines before starting treatment. ►FDA Drug safety announcement, 6 November 2015. Human papillomavirus vaccines: benefits outweigh risks E u r o p e a n U n i o n – The EMA has completed a detailed scientific review of the evidence surrounding reports of two syndromes, complex regional pain syndrome and postural orthostatic tachycardia syndrome in young women given human papillomavirus (HPV) vaccines. This review concluded that the evidence does not support a causal link between the vaccines (Cervarix®, Gardasil/Silgard® and Gardasil-9®) and development of either of the two syndromes. 457 WHO Drug Information Vol. 29, No. 4, 2015 Safety news More than 80 million girls and women worldwide have received HPV vaccines to protect them from cervical cancer and various other cancers and conditions caused by HPV. The EMA has confirmed that the benefits of these vaccines therefore continue to outweigh their risks, and that no changes to the product information are necessary. ►EMA Press release, 20 November 2015. Entacapone: no clear evidence of cardiovascular events ; U n i t e d S t a t e s o f A m e r i c a – Following concerns about a possible increased risk of heart attacks, stroke or other cardiovascular events associated with entacapone (Comtan®) and with the combination of entacapone, carbidopa and levodopa (Stalevo®), an FDA review has found no clear evidence of such a risk associated with the use of the two medicines. Entacapone-containing products are used to treat symptoms of Parkinson’s disease. In view of cardiovascular- related findings in clinical trials involving Stalevo®, the FDA had required the manufacturer to conduct an additional study, and had reviewed findings from this and another published study. ►FDA Drug safety communication, 26 October 2015. Removal of class warnings HIV medicines: class warnings about lipodystrophy and lactic acidosis removed E u r o p e a n U n i o n – HIV medicines will no longer require a warning concerning lipodystrophy, i.e. fat redistribution, in their product information, and a number of nucleoside and nucleotide analogues will no longer require a warning about lactic acidosis. Recent analyses show that only certain medicines cause fat changes, and that these fat changes concern lipoatrophy, i.e. the loss of subcutaneous fat. A specific warning related to lipoatrophy will remain in the product information for medicines containing zidovudine, stavudine and didanosine, and these medicines will also retain the lactic acidosis warning in line with current evidence. ►EMA Press release, 23 October 2015. Safety reviews started Medicine Use Concerns Reviewing authority reference Fusafungine- containing nasal and mouth sprays Treatment of upper airway infection Serious allergic reactions including anaphylactic reactions ►EMA. Start of review of nasal and mouth sprays containing Fusafungine. 11 September 2015. Tramadol Analgesic, not FDA-approved for use in children but being used off-label Rare but serious risk of slow or difficult breathing in children aged 17 years and younger ►FDA Drug safety communication, 21 September 2015. Safety news WHO Drug Information Vol. 29, No. 4, 2015 458 Packaging Improved packaging for dementia treatments ; U n i t e d K i n g d o m – The MHRA is working with the pharmaceutical industry to optimize the presentation of medicines for Alzheimer’s disease. To help patients retain independence in taking their medicines, the days of the week will be indicated clearly on the blister packs. The change is expected to help improve patient confidence, safety and treatment outcomes. The improved packaging will be introduced from June 2016. ►MHRA Press release, 3 November 2015. Medicines quality Apotex: Canada import ban lifted, product re-testing imposed C a n a d a – Health Canada has lifted the import restrictions imposed in September 2014 on products from the Indian companies Apotex Pharmachem India Pvt. Ltd. (APIPL) and Apotex Research Private Limited (ARPL), and has imposed re-testing of products from the two sites at an Apotex good manufacturing practices- compliant facility in Canada and reporting of any deficient results. In September 2015, Health Canada inspectors started being present in Apotex’s Canadian facility to inspect the operations and the testing of the products from India. In June 2015, Health Canada had inspected the corrective measures implemented at the Indian two sites and found that they have progressed in a satisfactory manner. Apotex Inc. has been requested to provide regular progress updates on the full and sustainable implementation of corrective actions at full production. Health Canada plans to re-inspect the sites in early 2016. ►Health Canada Advisory, 1 September 2015. Dibotermin alfa-containing implant kit: suspended in Europe; E u r o p e a n U n i o n – The EMA has recommended the suspension of a kit for implant containing a powder, solvent and absorbable collagen sponge (Inductos®) due to manufacturing-related quality issues. This follows a review triggered by observations during inspection of the manufacturing site, located in the United States, by Dutch and Spanish authorities. Although there is no indication of risk to patients directly linked to the inspection findings, the suspension will remain in force until the issues are addressed. The kit contains dibotermin alfa, a protein that helps with the formation of new bone tissue that grows into the sponge, which is gradually degraded by the body. Alternative treatments are available in the European Union. ►EMA Press release, 23 October 2015. 459 WHO Drug Information Vol. 29, No. 4, 2015 Safety news Falsified product alert The following text is reproduced from the WHO Medical Product Alert No. 5/2015. Falsified emergency contraceptive circulating in East Africa This Medical Product Alert relates to the confirmed circulation of falsified versions of Postinor-2 (Levonorgestrel) in East Africa. Postinor-2 is a widely used emergency contraceptive that should contain 0.75mg of levonorgestrel. The genuine product is manufactured by Gedeon Richter. In August 2015, the Uganda National Drug Authority notified WHO of the seizure of falsified Postinor-2 discovered in Kampala, Uganda. All packs reported bear the same batch number and expiry/manufacturing dates. The details of the product are as follows: • Product Name: Postinor-2 • Batch Number: T38012 • Manufacturing Date: 08 2013 • Expiry Date: 08 2018 There is a non-useable, white “scratch area” on the reverse side of the pack. The packaging is in English, French and Spanish languages. The batch number and manufacturing/expiry dates relate to a genuine batch of Postinor-2. Laboratory analysis has shown that the product contains zero active pharmaceutical ingredient. Furthermore, the manufacturers of genuine Postinor-2 have confirmed the packaging is falsified. If you are in possession of the same batch of Postinor-2 shown in the below photograph and with a non-useable white “scratch area” on the reverse side of the pack please do not use, contact a Pharmacist or a Doctor as soon as possible for advice and report the incident to your National Medicines Regulatory Authority. If you think you have taken this product, please seek medical advice immediately. If you have any information concerning the supply of this product please contact rapidalert@who.int ►WHO. Medical Product Alert N° 5/2015, 18 November 2015 (includes photograph). 460 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news Pre-market assessment Accelerated access pathways in Europe E u r o p e a n U n i o n – The EMA has sought public comments on its revised guidelines on the implementation of accelerated assessment and conditional marketing authorization (1). The revised guidelines provide more details on how to justify fulfilment of a major public health interest and on the importance of planning and early dialogue. More recently, EMA has also launched a public consultation on its new proposed PRIME scheme to optimize development of priority medicines and facilitate patients’ access (2). In their public input to the former consultation process (3), Health Action International (HAI), the International Society of Drug Bulletins (ISDB) and the Medicines in Europe Forum (MiEF) have emphasized the importance of concrete evidence demonstrating a new drug’s safety and therapeutic advance, of enforcing compliance with post-market obligations, and of ensuring transparency of accelerated decision-making by making assessment reports and expert statements publicly available. The three organizations have further published a joint briefing paper, in which they caution against adaptive pathways becoming the rule even when no genuine public health need exists (4). ► (1) EMA News, 27 July 2015. (2) EMA News, 26 October 2015. (3) HAI, ISDB, MiEF. Joint response to EMA public consultation. 30 September 2015. (4) “Adaptive licensing” or “adaptive pathways”: Deregulation under the guise of earlier access. Joint briefing paper. Brussels: HAI, ISDB, MiEF; 16 October 2015. Regulatory systems New Zealand working on new regulatory regime N e w Z e a l a n d – The New Zealand Government is working on a new and comprehensive national regulatory regime to regulate therapeutic products, i.e. the wide range products intended to be used in or on human beings for a therapeutic purpose including medical devices and cell and tissue therapies, which are currently not fully regulated in New Zealand. This follows the cessation of the Australia New Zealand Therapeutic Products Agency (ANZTPA) project. The intention is for a Bill to be introduced to Parliament in 2016. ►New Zealand Ministry of Health. Web page, updated 16 September 2015. Post-marketing control EMA initiative to improve patient registries E u r o p e a n U n i o n – The EMA has launched an initiative aimed at making better use of patient registries as a source of high-quality post-authorization data on medicines in clinical use. Registries collect information over time on patients who are diagnosed with a particular disease or who receive particular treatments. Some registries are kept by pharmaceutical companies as a 461 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news regulatory requirement, while others are operated at national or international levels for example by physicians’ associations or national agencies. Existing registries are not sufficiently coordinated or harmonized, leading to inefficiencies. The initiative is managed by a cross- committee task force and includes two components: a collaborative strategy and a pilot phase. The strategy aims to facilitate the interactions between coordinators of registries, regulators and pharmaceutical companies, and to identify methodological components for newly established registries to ensure that high quality and relevant data are collected. The pilot phase aims to test whether the strategy meets stakeholders’ needs on the basis of real-life examples. It is anticipated to last for two years. Participation will be determined on a case-by-case basis by the cross-committee task force. ►EMA News, 12 October 2015. Collaboration and harmonization ICH announces organizational changes G e n e v a – The International Council for Harmonisation (ICH), formerly known as the International Conference on Harmonisation, has announced organizational reforms to equip it better to face the challenges of global pharmaceutical development and regulation. The reforms aim to expand ICH beyond the current membership to make it a truly global initiative. Regulators around the world will be invited to join counterparts from Europe, Japan, USA, Canada and Switzerland as ICH regulatory members. This is matched by the possibility of wider inclusion of global industry sectors affected by ICH harmonization. ICH aims to be the leading platform for global pharmaceutical regulatory harmonisation, bringing together in a transparent manner all key regulatory authorities and industry stakeholders. The ICH operating structure will be an association under Swiss law, which establishes the new Assembly as the overarching governing body. ► ICH Press release, 26 October 2015. China and WHO collaborate on medicines quality G e n e v a – The long-standing collaboration between China and WHO to promote access to good quality pharmaceuticals was formalized in September 2015 when the Chinese Food and Drug Authority (CFDA) and WHO signed a ‘cooperation plan’ at WHO headquarters. The plan sets out a comprehensive package of measures that China will undertake with WHO’s technical assistance, specifically to improve the quality of generic medicines, create a more science based and efficient review and approval system, reduce drug submission backlogs and promote transparency of operations. ►WHO Essential medicines and health products. China – growing potential to supply affordable quality medicines [web page]. Meeting of World Pharmacopoeias held in China C h i n a – The 6th International Meeting of World Pharmacopoeias was co-hosted by the Chinese Pharmacopoeia (ChP) and WHO in Suzhou, China, on 21–22 September 2015. Achieving global standards to expand access to quality medicines globally was key to the discussions of the meeting, which was Regulatory news WHO Drug Information Vol. 29, No. 4, 2015 462 held in connection with the 2015 ChP Annual Scientific Symposium. Twelve pharmacopoeias from all around the globe attended, including the European Pharmacopoeia on behalf of its 38 signatories. An important output of this international meeting was the finalization of the first- ever guideline on Good Pharmacopoeial practices, based on feedback received during wide global consultation, for presentation to the WHO Expert Committee on Specifications for Pharmaceutical Preparations. The Committee’s adoption of this guideline at its 50th meeting in October 2015 (see also page 481) marks a significant step forward in setting globally unified principles for creating quality standards for medicines. ►WHO Essential medicines and health products. Meeting of World Pharmacopoeias in China benefits the world’s [web page]. Regulators of United Kingdom and India sign agreement N e w D e l h i – The Medicines and Healthcare products Regulatory Agency (MHRA) and the Central Drugs Standard Control Organisation (CDSCO) under the Ministry of Health and Family Welfare of the Republic of India have signed a Memorandum of Understanding (MOU). The agreement aims to facilitate regulatory information exchange and technical cooperation of mutual benefit, helping to protect the health and public safety in the two countries. In 2014, MHRA carried out 125 inspections in non-EU countries, 49 of which were in India. Approximately 25% of the medicines sold in the United Kingdom are made in India. The agreement is part of a concerted effort to promote good manufacturing practices throughout the pharmaceutical industry, benefitting the global public. Similar agreements are already in place between MHRA and counterpart bodies in China and America. ►MHRA Press release, 5 October 2015. EMA and WHO share non-public information E u r o p e a n U n i o n – The European Commission, EMA and WHO have concluded a working arrangement that allows timely sharing of non-public information on the safety, quality and efficacy of medicines already authorized or under review in the European Union (EU), or prequalified or under review by WHO. This cooperation started on 1st September 2015. The arrangement will make it easier and quicker to communicate and take action to protect public health. Examples of information that may be shared include: • pharmacovigilance data, particularly urgent information on EU-originating or non-EU originating adverse reactions; • information on applications for scientific advice, orphan medicine designation, marketing authorization, post- authorization activities of significant public health interest, and applications for agreement of paediatric investigation plans; and • data and reports related to inspections, manufacturing facilities and clinical research activities. ►EMA News, 22 September 2015. 463 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news Approved Insulin degludec & insulin aspart: for diabetes mellitus Product name: Ryzodeg 70/30® Dosage form: Injection Class: Combination of a long-acting insulin analog (insulin degludec) and a rapid- acting human insulin analog (insulin aspart): ATC code: A10AD06 Approval: FDA Use: Improvement of glycaemic control in adults with type 1 and 2 diabetes mellitus Benefits: Additional treatment option for diabetes; ability to reduce HbA1c equivalent to reductions achieved with FDA-approved long-acting or pre-mixed insulin products. Safety information: The product should not be used in patients with diabetic ketoacidosis. Like other insulins, it may cause severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock, as well as hypoglycaemia which can be life-threatening. Notes: The FDA has also approved insulin degludec (Tresiba®) which was approved by EMA in 2013. ►FDA News release, 25 September 2015. Efmoroctocog alfa: for haemophilia A Product name: Elocta® Dosage form: Powder and solvent for solution for injection Class: Antihaemorrhagic (ATC code: B02) Approval: EMA (orphan designation) Use: Treatment and prophylaxis of bleeding in patients with haemophilia A Benefits: provide adequate prophylaxis in terms of annualised bleeding Benefits: Ability to provide adequate prophylaxis in terms of annualised bleeding rate, to control bleeding on demand and to provide haemostatic efficacy for surgical procedures. Safety information: Hypersensitivity reactions have been reported rarely. ►EMA/CHMP Summary of opinion, 24 September 2015. Modified antihaemophilic factor (recombinant) Product name: Adynovate® Dosage form: Lyophilized powder for solution for intravenous injection. Class: Blood coagulation factor Approval: FDA Use: On-demand treatment and control of bleeding episodes for prophylaxis in patients with haemophilia A. Benefits: This PEGylated product potentially requires less frequent injections than unmodified antihaemophilic factor. ►FDA News release, 13 November 2015. Coagulation Factor X (human): for hereditary Factor X deficiency Product name: Coagadex® Class: Blood coagulation factor; ATC code: B02BD13 Approval: FDA (orphan designation) Use: Treatment of individuals aged 12 and older with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in patients with mild hereditary Factor X deficiency. Benefits: The availability of a purified Factor X concentrate increases treatment options for patients with this rare hereditary condition. ►FDA News release, 20 October 2015. Patiromer : for hyperkalaemia Product name: Veltassa® Dosage form: Powder for oral suspension Class: Potassium binder; polymer Approval: FDA Use: Treatment of hyperkalaemia. Not appropriate for rapid correction of severe Regulatory news WHO Drug Information Vol. 29, No. 4, 2015 464 Approved hyperkalaemia as lowering of serum potassium may take hours to days. Benefits: In clinical trials, patiromer was effective in lowering potassium levels in hyperkalaemic participants with chronic kidney disease taking one or more renin- angiotensin-aldosterone system inhibitors. Safety information: Patiromer binds many other orally administered drugs, which could decrease their absorption and reduce their effects. It should be taken at least six hours before or after any other orally administered medication. ►FDA News release, 21 October 2015. Elvitegravir & cobicistat & emtricitabine & tenofovir alafenamide : for HIV infection Product name: Genvoya® Dosage form: Film-coated tablet Class: Antiretroviral, fixed-dose combination; ATC code: J05AR18 Approval: EMA Use: Treatment of adults and adolescents infected with human immunodeficiency virus 1 without any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or tenofovir Benefits: Potent antiretroviral response in a once daily, single pill regimen; lower impact on renal safety and bone mineral density than tenofovir disoproxil. ►EMA/CHMP Summary of opinion, 24 September 2015. Uridine triacetate : for a rare hereditary metabolic disorder Product name: Xuriden® Dosage form: Oral granules Class: Nucleoside Approval: FDA (orphan drug designation) Use: Treatment of hereditary orotic aciduria, a very rare metabolic disorder that prevents the body from synthesizing uridine, a necessary component of ribonucleic acid (RNA). This causes blood count disorders and urinary tract obstruction due to the formation of orotic acid crystals, resulting in failure to thrive and developmental delays. Benefits: Uridine replacement; stabilisation of the haematologic parameters. ►FDA News release, 4 September 2015. Trifluridine & tipiracil: for advanced colorectal cancer Product name: Lonsurf® Dosage form: Tablet Class: combination of a nucleoside metabolic inhibitor (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil); ATC code: L01BC59 Approval: FDA Use: Treatment of patients with advanced (metastatic) colorectal cancer who have been previously treated with chemotherapy and biological therapy. Benefits: Additional treatment option for metastatic colorectal cancer. Safety information: Risk of severe myelosuppression. Complete blood counts should be obtained before starting each treatment cycle, and patients should be monitored throughout treatment. Women should be advised of potential risks to developing foetuses. Women on treatment with this product should not breastfeed. ►FDA News release, 22 September 2015. Blinatumomab: for certain acute lymphoblastic leukaemias Product name: Blincyto® Dosage form: Powder in a vial for preparing a concentrate for solution for infusion, and stabilising solution Class: Bispecific T-cell engager antibody; ATC code: L01XC19 Approval: EMA (conditional marketing authorization; orphan designation) Use: Treatment of adults with Philadelphia chromosome-negative relapsed or 465 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news Approved refractory B-precursor acute lymphoblastic leukaemia. Benefits: Ability to increase the proportion of patients who have complete remission and molecular remission within the first two treatment cycles. ►EMA CHMP Summary of opinion, 24 September 2015. Necitumumab : for advanced squamous non-small cell lung cancer Product name: Portrazza® Dosage form: Class: monoclonal antibody, EGFR-blocker: ATC code: L01XC22 Approval: FDA Use: Treatment of patients with advanced (metastatic) squamous non-small cell lung cancer who have not previously received medication specifically for this cancer. Benefits: New treatment option for certain patients with squamous cell lung cancer, ability to extend survival. Safety information: The product carries a boxed warning to alert health care providers about serious risks of cardiac arrest and sudden death, as well as hypomagnesaemia with potentially fatal outcomes. ►FDA News release, 24 November 2015. Cobimetinib: for metastatic melanoma Product name: Cotellic® Dosage form: Film-coated tablets Class: Antineoplastic agent; mitogen- activated protein kinase (MAPK) pathway inhibitor (ATC code: L01XE) Approval: EMA, FDA (priority review; orphan drug designation) Use: In combination with vemurafenib, treatment of unresectable or metastatic melanoma in patients with a BRAF V600 mutation Benefits: Longer progression-free survival in melanoma patients with a BRAFV600 mutation, compared with vemurafenib monotherapy. Safety information: May cause severe side effects including cardiomyopathy, rhabdomyolysis, new skin tumours, retinal detachment, liver damage, bleeding and severe skin rash due to photosensitivity. Women taking cobimetinib should use effective contraception. Notes: The product was first approved by Swissmedic in August 2015. ►EMA CHMP Summary of opinion, 24 September 2015. FDA News release, 10 November 2015. Irinotecan liposome injection: for advanced pancreatic cancer Product name: Onivyde® Dosage form: Liposome injection Class: Antineoplastic agent; ATC code: L01XX19 Approval: FDA (orphan designation; priority review) Use: In combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have been previously treated with gemcitabine- based chemotherapy. Benefits: Longer survival period, compared to patients treated with fluorouracil and leucovorin only. Safety information: The medicine carries a Boxed Warning about the risks of severe neutropenia and diarrhoea. Death due to sepsis following neutropenia has been reported in patients treated with irinotecan. The medicine is not FDA-approved for use as a single agent. ►FDA Press announcement, 22 October 2015. Carfilzomib: for a rare type of blood cancer Product name: Kyprolis® Dosage form: Powder for solution for injection Regulatory news WHO Drug Information Vol. 29, No. 4, 2015 466 Approved Class: Irreversible proteasome inhibitor; ATC code: L01XX45 Approval: EMA (accelerated assessment, orphan designation) Use: In combination with lenalidomide and dexamethasone, treatment of adult patients with multiple myeloma who have received at least one prior therapy. Benefits: More sustained inhibition of targeted proteasome with minimal inhibition of other non-targeted enzymes; longer progression-free interval. Safety information: Serious side effects include blood abnormalities and cardiac events. A follow-up plan was approved to monitor the safety and efficacy of carfilzomib. ►EMA Press release, 25 September 2015. Ixazomib: for multiple myeloma Product name: Ninlaro® Dosage form: Capsule Class: Antineoplastic – first oral proteasome inhibitor; ATC code: L01XX50 Approval: FDA (orphan drug designation; priority review) Use: In combination lenalidomide and dexamethasone, to treat patients with multiple myeloma who have received at least one prior therapy. Benefits: New oral treatment with ability to slow disease progression when other therapy has failed. ►FDA News release, 20 November 2015. Talimogene laherparepvec : for advanced melanoma Product name: Imlygic® Dosage form: Solution for injection Class: Oncolytic virus derived from HSV-1 (a first-in-class advanced therapy medicinal product) Approval: EMA, FDA Use: Treatment of adults with unresectable melanoma. The product is directly injected into lesions in the skin or lymph nodes. Benefits: Increased durable response rate – defined as disappearance of the tumours or at least 50% reduction of tumours lasting at least six months – compared to treatment with the immune stimulatory protein human GM-CSF. The product has not been shown to improve overall survival or to have an effect on melanoma that has spread to the brain, bone, liver, lungs, or other internal organs. Safety information: This product is a modified live oncolytic herpes virus therapy, therefore herpes virus infection can occur. Given this, the product should not to be used in patients who are immunocompromised, or in pregnant women. ►EMA Press release, 23 October 2015. FDA News release, 27 October 2015. Mepolizumab: for asthma Product name: Nucala® Dosage form: Powder for solution for injection Class: Humanised monoclonal antibody targeting human interleukin-5; ATC code: L04AC06 Approval: EMA, FDA Use: Treatment of patients 12 years and older with severe refractory eosinophilic asthma. Benefits: Can reduce the number of asthma exacerbations in patients who either remain uncontrolled on their previous standard of care or who are dependent on systemic corticosteroids. Safety information: Hypersensitivity reactions can occur within hours or days of treatment. ►EMA/CHMP Summary of opinion, 24 September 2015. FDA News release, 4 November 2015. Osimertinib: for certain non-small cell lung cancers Product name: Tagrisso® Dosage form: Tablet 467 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news Approved Class: Third-generation tyrosine kinase inhibitor Approval: FDA (breakthrough therapy designation, priority review and orphan drug designation; accelerated approval. Continued approval for this indication may be contingent upon further confirmatory studies.) Use: Treatment of patients with advanced non-small cell lung cancer whose tumours have the T790M epidermal growth factor receptor (EGFR) mutation and have progressed on or after treatment with other EGFR-blocking therapy. Benefits: Reduction of tumour size was observed in more than half of the patients treated in two clinical trials. Safety information: May cause serious side effects, including inflammation of the lungs and injury to the heart. May cause harm to a developing foetus. Notes: The FDA also approved a companion diagnostic test (cobas EGFR Mutation Test v2) to detect the T790M mutation. ►FDA News release, 13 November 2015. Daratumumab : for multiple myeloma Product name: Darzalex® Dosage form: Injection for intravenous use Class: Antineoplastic; human CD38-directed monoclonal antibody Approval: FDA (breakthrough therapy designation, priority review and orphan drug designation; accelerated approval) Use: Treatment of treat patients with multiple myeloma who have received at least three prior treatments. Benefits: Ability to achieve complete or partial reduction in tumour burden. Safety information: Daratumumab may cause serious infusion reactions. Daratumumab may interfere with certain tests that are done by blood banks (such as antibody screening) for patients who need a blood transfusion. ►FDA News release, 16 November 2015. Cariprazine : for schizophrenia and bipolar disorder Product name: Vraylar® Dosage form: Capsules Class: Antipsychotic, ATC code: N05AX15 Approval: FDA Use: Treatment of schizophrenia and bipolar disorder in adults Benefits: Reduction of symptoms of schizophrenia and bipolar disorder Safety information: As all other FDA- approved products for treatment of schizophrenia and bipolar disorder, the product has a Boxed Warning about an increased risk of death associated with the use of these drugs in older people with dementia-related psychosis. Neither cariprazine nor any other drug in this class is approved to treat such patients. ►FDA News release, 17 September 2015. Pitolisant: for narcolepsy Product name: Wakix® Dosage form: Film-coated tablets Class: Antagonist/inverse agonist of the histamine H3 receptor (first-in-class); ATC code: N07XX11 Approval: EMA (orphan designation) Use: Treatment of adult patients with narcolepsy with or without cataplexy. Narcolepsy is a rare, long-term sleep disorder which affects the brain’s ability to regulate the normal sleep-wake cycle, and may occur with or without cataplexy (sudden severe muscle weakness or loss of muscle control). Benefits: Ability to reduce excessive daytime sleepiness in patients with narcolepsy, and to decrease cataplexy rate. ►EMA Press release, 20 November 2015. Naloxone nasal spray : for opioid overdose Product name: Narcan® Dosage form: Nasal spray Class: Antidote; ATC code: V03AB15 Regulatory news WHO Drug Information Vol. 29, No. 4, 2015 468 Approved Approval: FDA (fast-track designation, priority review) Use: To reverse the effects of an opioid overdose. Benefits: Easier to deliver than injectable dosage form, with no risk of a contaminated needle stick. ►FDA News release, 18 November 2015. Idarucizumab: for reversal of dabigatran anticoagulant effect Product name: Praxbind® Dosage form: Solution for injection/infusion Class: Humanised monoclonal antibody fragment; ATC code: V03AB Approval: EMA Use: Indicated in adult patients treated with dabigatran etexilate (Pradaxa®) when rapid reversal of the latter’s anticoagulant effects is required: (1) for emergency surgery/urgent procedures or (2) In life- threatening or uncontrolled bleeding. For hospital use only. Benefits: Ability to reverse the anticoagulant effect of dabigatran within 5 minutes of administration, enabling clinical emergency management of patients if needed. Does not interfere with routine treatment in case of bleeding or urgent surgery. ►EMA Press release, 25 September 2015. Patiromer : for hyperkalaemia ; Product name: Veltassa® Dosage form: Powder for oral suspension Class: Potassium binder; polymer Approval: FDA Use: Treatment of hyperkalaemia. Not appropriate for rapid correction of severe hyperkalaemia because lowering of serum potassium may take hours to days. Benefits: In clinical trials, patiromer was effective in lowering potassium levels in hyperkalaemic participants with chronic kidney disease taking one or more renin- angiotensin-aldosterone system inhibitors. Safety information: Patiromer binds many other orally administered drugs, which could decrease their absorption and reduce their effects. It should be taken at least six hours before or after any other orally administered medication. ►FDA News release, 21 October 2015. EMA Article 58 positive opinion Pyronaridine-artesunate – paediatric antimalarial formulation Product name: Pyramax® Additional dosage form: Granules for oral suspension Class: Antimalarial, artemisinin combination therapy Approval: EMA positive opinion under Article 58. This programme allows the EMA to assess and give a scientific opinion in cooperation with the World Health Organization (WHO) for medicines intended exclusively for markets outside the European Union (EU). Through this mechanism, regulators outside the EU can use the CHMP assessment as part of their national authorisation process. Newly approved use: Treatment of malaria caused by P. falciparum and P. vivax in children and infants weighing 5 kg to less than 20 kg under 20 kg. Restrictions were also removed on repeated courses of treatment in patients and on its use only in areas of low malaria transmission with evidence of artemisinin resistance. Note: This artemisinin combination therapy was first evaluated as film-coated tablets in 2012 and received a positive opinion under EMA’s Article 58 programme. (1) 469 WHO Drug Information Vol. 29, No. 4, 2015 Regulatory news Approved This paediatric antimalarial formulation as well as the film-coated tablet formulation for adults and children weighing >20kg were developed by the product development partnership Medicines for Malaria Venture (MMV) and Shin Poong Pharmaceutical Co. Ltd., Republic of Korea. (2) ► (1) EMA/CHMP Summary of opinion, 19 November 2015. (2) MMV Press release, 20 November 2015. Extensions of indications Anthrax vaccine adsorbed : for post- exposure protection Product name: BioThrax® Dosage form: Suspension for intramuscular or subcutaneous injection Class: Anthrax vaccine; ATC code: J07AC Approval: FDA Newly approved use: Together with antibiotic treatment, to prevent disease after confirmed or suspected exposure to anthrax spores. ►FDA News release, 23 November 2015. Ipilimumab: to prevent melanoma recurrence Product name: Yervoy® Dosage form: Injection for intravenous infusion Class: Antineoplastic, monoclonal antibody that blocks CTLA-4; ATC code: L01XC11 Approval: FDA Newly approved use: Adjuvant therapy for patients with stage III melanoma, to lower the risk that the melanoma will return following surgery. Safety information: The product carries a Boxed Warning about potential fatal immune-mediated adverse reactions and unusual severe side effects. ►FDA News release, 28 October 2015. Nivolumab: for renal cell cancer Product name: Opdivo® Dosage form: Concentrate for solution for infusion Class: Antineoplastic agent, monoclonal antibody, PD-1 receptor blocker; ACT code: L01XC17 Approval: FDA (breakthrough therapy designation, fast track designation, priority review) Newly approved use: Treatment of patients with advanced (metastatic) renal cell carcinoma who have received prior anti- angiogenic therapy. ►FDA News release, 23 November 2015. Pembrolizumab: for advanced non- small cell lung cancer ; Product name: Keytruda® Dosage form: For injection: lyophilized powder in single-use vial for reconstitution Class: Antineoplastic; PD-1 pathway blocker; ATC code: L01XC18 Approval: FDA (breakthrough therapy designation, accelerated approval). Approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non-small cell lung tumours. Newly approved use: Treatment patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and whose tumours express the PD-L1 protein. Notes: Pembrolizumab was previously approved for advanced melanoma by FDA and EMA. ►FDA News release, 2 October 2015. WHO endorsements Global Ebola virus and antibody reference standards The WHO Expert Committee on Biological Standardization has endorsed two types of Ebola reference reagents as the global Regulatory news WHO Drug Information Vol. 29, No. 4, 2015 470 WHO endorsements standards for use in laboratory tests. The reference reagents were developed within a short time by the National Institute for Biological Standards and Control (NIBSC) and are made available to laboratories around the world through the NIBSC web site (www.nibsc.org/products/brm_product_ catalogue.aspx). The first standard is used for testing alongside patient samples to detect Ebola infection. The second measures Ebola antibody levels following infection, or following immunization with candidate vaccines. The two standards will enable accurate measurement of Ebola virus and antibody, making it possible to compare results from different tests and different laboratories. By minimizing fragmentation and duplication of research efforts these global standards will help accelerate the development of new Ebola vaccines. ►MHRA Press release, 5 November 2015. Malaria vaccine to be delivered in pilot projects The World Health Organization’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) jointly recommended the implementation of 3–5 large pilot projects to understand how best to deliver a vaccine that protects against malaria in young children. The vaccine must be given in three doses one month apart, followed by a fourth dose 18 months later. The main question is how to ensure that each child receives all four doses. The vaccine, known as RTS,S or Mosquirix®, was approved in July 2015 by EMA under its Article 58 procedure for medicines used outside the EU, subject to WHO recommendations on its use. It acts against P. falciparum, the most deadly malaria parasite globally and the most prevalent in Africa. It offers no protection against P. vivax malaria, which predominates in many countries outside Africa. The vaccine is a complementary tool that could be added to – but not replace – the core package of proven measures to prevent, diagnose and treat malaria. ►WHO News release, 23 October 2015. æ 471 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events Development Sustainable development goals aim at health for all G e n e v a – WHO has welcomed the launch of the 2030 Agenda for Sustainable Development and is committed to work with partners around the world to achieve the new Sustainable Development Goals (SDGs). Building on the Millennium Development Goals (MDGs), the SDG agenda demonstrates unprecedented scope and ambition. Poverty eradication, health, education, and food security and nutrition remain priorities, but the 17 SDGs also encompass a broad range of economic, social and environmental objectives, as well as the promise of more peaceful and inclusive societies. SDG 3, “Ensure healthy lives and promote well-being for all at all ages”, profiles health as a desirable outcome in its own right. However, health is also presented as an input to other goals, and a reliable measure of how well sustainable development is progressing in general. The health goal includes new targets for key issues such as the global HIV, tuberculosis and malaria epidemics as well as child mortality and maternal mortality, on which major progress has been made under the MDGs. It also covers non-communicable diseases; health security; reproductive, maternal, newborn, child and adolescent health and infectious diseases, as well as universal health coverage – a goal which WHO particularly welcomes as it expresses the very spirit of the new development agenda, with its emphasis on equity and social inclusion that leaves no one behind. ►WHO Statement, 25 September 2015. Access to medicines WHO publishes updated essential medicines lists G e n e v a – WHO has published its updated WHO Model Lists of Essential Medicines and Essential Medicines for Children (1). A range of direct-acting anti- viral medicines for hepatitis C (sofosbuvir, simeprevir, daclatasvir, ledipasvir and ombitasvir) have been added, despite the high cost of some of these medicines. This inclusive approach aims to enable the selection of optimal treatment regimens and to promote competition. Four medicines for treatment of multi-drug resistant tuberculosis have also been added, including the first new medicines to be developed for this disease in decades (bedaquiline and delamanid). The list further includes 16 new and 30 existing cancer medicines that were found to be associated with substantial or highly relevant benefits. The report specifies the evidence upon which the decisions were taken. The model list will influence the development of national Essential Medicines Lists worldwide. The authors of a comment published in The Lancet (2) have welcomed the report, noting that the concept of selecting a limited list of essential medicines is applicable across countries and settings as a means to implement the moral imperative of Publications and events WHO Drug Information Vol. 29, No. 4, 2015 472 assuring universal access to life-saving medicines. They further emphasized the importance of comprehensive essential medicine policies covering a wide range of aspects, such as appropriate research and development, financing mechanisms, generic policies including various measures to overcome patent barriers, quality assurance, supply systems, and safe and cost-effective use. The 2016 report of the Lancet Commission on Essential Medicines Policies (3) will recommend ways of implementing such policies through concrete actions at the national and global levels. ► (1) WHO Technical Report Series. The Selection and Use of Essential Medicines. Report of the WHO Expert Committee, 2015 (including the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines for Children). October 2015. Published online in advance of publication in print. (2) Gray AL, Wirtz VJ, ‘t Hoen E, Reich MR, Hogerzeil HV. Essential medicines are still essential. The Lancet. 2015; 386:1601–3. DOI: http://dx.doi.org/10.1016/S0140- 6736(15)00514-0. (3) The Lancet. A new Lancet Commission on essential medicines. Lancet 2014; 384: 1642. DOI: http://dx.doi.org/10.1016/S0140- 6736(14)62017-1 Medicines Patent Pool expands mandate to hepatitis C and tuberculosis G e n e v a – The Medicines Patent Pool (MPP), the world’s only voluntary licensing mechanism in public health, has announced an expansion of its mandate to hepatitis C and tuberculosis medicines. Hepatitis C affects between 130 and 150 million people worldwide. Tuberculosis killed 1.5 million people globally in 2014 alone and has become a public health challenge particularly with the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. New treatments have been developed for both diseases, but they are unaffordable for many health systems. Since its creation in 2010, the MPP has signed agreements for 12 antiretrovirals with six patent holders for countries that are home to 87-93% of people living with HIV in the developing world, saving the international community an estimated $119.6 million from the procurement of low-cost HIV medicines. Building on its existing model, the MPP will seek to license for generic manufacture of new direct acting antivirals for hepatitis C as well as new and re-purposed medicines for tuberculosis. ►MPP Press release, 6 November 2015. First patent pool licence for a hepatitis C medicine G e n e v a – The Medicines Patent Pool (MPP) has signed a licence with Bristol-Myers Squibb for the hepatitis C medicine daclatasvir. The royalty-free agreement allows manufacturers to develop daclatasvir for sale in 112 low- and middle-income countries, 76 of which are classified as middle-income nations by the World Bank. Nearly two thirds of all patients living with hepatitis C in the LMICs reside in the territory covered by this agreement. Importantly, the licence allows generic manufacturers to develop fixed-dose combinations with other direct-acting antivirals to create powerful pan-genotypic regimens that offer the potential to treat all of the six major genotypes of HCV. Pan-genotypic regimens are crucial in resource-limited countries where access to genotype testing is limited. Bristol- Myers Squibb will provide a technology 473 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events transfer package and information needed for the manufacture and registration of the product. As all licences signed by the MPP, the full agreement is available on the MPP’s website. MPP Press release, 23 November 2015. Controlled substances not accessible to all in need K u a l a L u m p u r – The Global Commission on Drug Policy (GCDP) has released a new report showing that 75% of the world’s population does not have access to pain-relieving medicines included in the WHO Model List of Essential Medicines, because of strict drug control policies. Ninety-two percent of the world’s supply of morphine is consumed by just 17% of the global population, with consumption primarily concentrated in North America and Europe. The report notes that governments have an obligation under international law to ensure equitable access to controlled medicines for their populations, and that this obligation has equal importance as drug control measures to reduce illegal diversion. The upcoming UN General Assembly Special Session (UNGASS) on Drugs in New York in April 2016 will be an opportunity to address this major gap in access to controlled medicines. (1) Aside from morphine and other opioid analgesics, ketamine – an anaesthetic – is one of the needed substances. In March 2015 a UN Commission vote on whether ketamine should be placed under international control had been postponed. The WHO Expert Committee on Drug Dependence (ECDD) has recommended against this measure on three separate occasions, in 2006, 2012 and 2014. In response to a request for more information from the UN Commission on Narcotic Drugs, the WHO Expert Committee considered updated evidence on the issue at its 37th meeting on 16-20 November 2015. The material presented to the Committee confirmed the importance of the medical use of ketamine, particularly for low and middle income countries, and highlighted the potential role of ketamine as a prototype for a completely new class of antidepressants. The report did not find any changes with regard to global ketamine use and related medical problems, or abuse liability or toxicity. (2) ► (1) 24th International harm reduction conference, 18-21 October 2015, Kuala Lumpur, Malaysia. Press release, 19 October 2015. Global Commission on Drug Policy. The Negative Impact of Drug Control on Public Health: The Global Crisis of Avoidable Pain. October 2015. (2) Ketamine (INN). Update Review Report. Agenda item 6.1. Expert Committee on Drug Dependence, Thirty-seventh Meeting. Geneva, 16-20 November 2015. Inefficiencies in the global insulin market Health Action International (HAI) has released its first fact sheet from the ACCISS (Addressing the Challenges and Constraints of Insulin Sources and Supply) Study, which shows that one in two people in need of insulin cannot reliably access this life-saving medication because it is unavailable, unaffordable or both. The fact sheet provides an overview of the increasing global need for insulin to treat type 1 and type 2 diabetes and describes some of the barriers at national and global level that prevent millions of people from accessing insulin. The three-year study, which was launched in early 2015, aims to identify the causes of poor insulin availability and unaffordable prices as a basis for Publications and events WHO Drug Information Vol. 29, No. 4, 2015 474 developing policies and interventions to improve access, particularly in the world’s most under-served regions. ►ACCISS/HAI. Inequities and Inefficiencies in the Global Insulin Market. Fact Sheet 1. 1st November 2015. Health and trade European Council resolution defends public health interests S t r a s b o u r g – The Parliamentary Assembly of the Council of Europe has adopted a resolution titled “Public health and the interests of the pharmaceutical industry: how to guarantee the primacy of public health interests?” The resolution recognizes the indisputable role that the pharmaceutical industry has played in medical advances. However, it notes that in recent years very few new medicines have been placed on the market which present “a real therapeutic benefit satisfying real health needs.” Prices for some medicines, such as cancer and hepatitis C treatments, have increased sharply placing a burden on public health systems. The resolution calls on member states to apply rules to limit rising prices and conflicts of interest. It also proposes to set up a public fund for independent research geared to address unmet health needs, and calls on the WHO to put forward alternatives to the current patent-based model for development of new medicines. ► Intellectual Property Watch. Council Of Europe Issues Resolution, Questions Current IP System For Pharmaceutical Products. 1st October 2015. Parliamentary Assembly of the Council of Europe. Resolution 2071 (2015) Provisional version. HAI/MSF report on EU trade policies and public health B r u s s e l s – Médecins sans Frontières (MSF) and Health Action International (HAI) have launched their new report reviewing the European trade and investment policies, and have urged the European Union (EU) to close the gap between its public position to support access to affordable medicines and the current reality of its trade policies. The report recommends that countries should be supported in making use of the public health related flexibilities of the TRIPS Agreement to promote access to medicines. The report comes as the European Trade Commissioner has presented her future trade and investment strategy. The European Commission has recently decided to support the world’s poorest countries in their request for an indefinite exemption from implementing intellectual property rules on medicines until they are no longer classified as a least-developed country. ►HAI / MSF Press release, 14 October 2015. HAI / MSF Access Campaign. Empty gestures: The EU’s commitments to safeguard access to medicines. Review of the European Union’s Trade & Investment Policy, 2015. WTO extends drug patent exemption for least-developed countries G e n e v a – The World Trade Organization (WTO)’s Council for Trade-Related Aspects of Intellectual Property Rights (TRIPS) has agreed to extend until 2033 the period during which key provisions of the WTO’s intellectual property agreement, the TRIPS Agreement, do not apply to pharmaceutical products in least-developed countries. The 475 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events decision also keeps open the option for further extensions beyond that date. The extension comes a month after the adoption of the new UN Sustainable Development Goals (SDGs), which affirm the right of developing countries to utilize TRIPS Agreement flexibilities to ensure access to medicines for all. ►WTO News item, 6 November 2015. New WHO publication about trade and health G e n e v a – A new WHO publication explores the linkages between trade and health in today’s globalized world, and the strategies that policy-makers can adopt in order to harness trade-related benefits and mitigate negative impacts in order to promote public health. It provides background information, makes recommendations for coherent policy- making on trade and health, reviews recent initiatives in trade and health capacity building and offers technical advice, from a public health perspective, on the implementation of trade treaties in national legislation. The book concludes with three chapters on sector-specific intersections between health and trade, including a chapter on trade in medicines, which examines the impact of trade- related mechanisms – especially aspects related to intellectual property protection – on medicines availability, and policy instruments used in different countries to strike a balance between public health and commercial interests. ►Trade and Health: Towards building a National Strategy. Geneva: WHO, 2015. Diseases Hepatitis world summit adopts Declaration Glasgow - Over 400 global stakeholders representing over 90 countries gathered at the first-ever World Hepatitis Summit held in Glasgow on 2-4 October 2015 (1). Concluding the summit, the participants released the Glasgow Declaration on Hepatitis (2), which calls upon governments to develop and implement comprehensive, funded national plans and programmes for prevention, testing, diagnosis, care and treatment of hepatitis. Around 400 million people are currently living with viral hepatitis. Claiming an estimated 1.45 million lives each year, the disease is one of the world’s leading causes of death. The draft WHO Global Health Sector Strategy on Viral Hepatitis (3) proposes targets for reduction of incidence and mortality, and aims for treatment of 80% of eligible people with chronic hepatitis B and C infections. Medicinal treatments exist, but funding is the big question in view of their current high cost. ► (1) WHO. Hepatitis. First World Hepatitis Summit [web page]. (2) Glasgow Declaration on Hepatitis. (3) WHO Global Health Sector Strategy on Viral Hepatitis, 2016-2021. Draft for consultation. Malaria death rates plunge but risk remains L o n d o n – WHO and UNICEF have launched their joint report on achieving the malaria millennium development goals (MDGs) (1). The report (2) summarizes the remarkable progress seen in reversing malaria mortality and incidence. Between Publications and events WHO Drug Information Vol. 29, No. 4, 2015 476 2000 and 2015, malaria incidence fell by 37% globally and death rates by 60%. New research from the Malaria Atlas Project – a WHO Collaborating Centre based at the University of Oxford – shows that insecticide-treated nets have been by far the most important intervention across Africa (3). However, serious bottlenecks remain in providing full access to malaria prevention, diagnostic testing and treatment. Progress has been uneven: fifteen countries – mainly in sub-Saharan Africa – bear the burden of 80% of malaria cases globally. Children under five account for more than two thirds of all malaria-associated deaths. The World Health Assembly’s 15-year road map for malaria control aims at a further 90% reduction in global malaria incidence and mortality by 2030. The WHO-UNICEF report notes that these targets can only be achieved with political will, country leadership and significantly increased investment. Annual funding will need to triple, from US$ 2.7 billion today to US$ 8.7 billion in 2030. ► (1) WHO/UNICEF joint press release, 17 September 2015. (2) Achieving the malaria MDG target: reversing the incidence of malaria 2000– 2015. WHO, UNICEF: September 2015. (3) Bhatt S et al. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature (2015) doi:10.1038/nature15535. Published online, 16 September 2015. Tuberculosis remains a public health challenge G e n e v a – The WHO has released its Global tuberculosis report 2015. The report shows a continuing decline in mortality, which has nearly halved since 1990. The number of new cases reported globally has fallen by 1.5% each year for a total decrease of 18% since the year 2000. The millennium development goal to halt and reverse tuberculosis incidence by 2015 has been achieved globally and in 16 of the 22 high-burden countries that collectively account for 80% of cases. However, tuberculosis remains a public health challenge. Tuberculosis and HIV now rank alongside each other as the infectious diseases with the highest numbers of deaths in the world. Each accounted for 1.1–1.2 million deaths in 2014. To reduce the global burden of tuberculosis, detection and treatment gaps need to be closed, funding shortfalls filled and new diagnostics, medicines and vaccines developed. Detection and treatment gaps are especially serious among people with multidrug-resistant tuberculosis. Only about a quarter of an estimated 480 000 cases worldwide were detected and reported to national authorities in 2014. The major reason for these gaps is a shortfall in funding. ►WHO News release, 20 October 2015. WHO. Global tuberculosis report 2015. 20th Edition. Geneva: 2015. Ebola still a public health emergency G e n e v a – At its 7th meeting, the Emergency Committee convened by the WHO Director-General under the International Health Regulations has advised that the Ebola virus disease (EVD) outbreak continues to constitute a public health emergency of international concern. Two active chains of transmission continued in October 2015, one in Guinea and one in Sierra Leone. The Committee has updated its recommendation on measures to minimize the risk of international spread of EVD. 477 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events There should be no international travel of Ebola contacts or cases unless they are part of appropriate medical evacuation, and exit screening should be performed at the borders of States with Ebola transmission. On the other hand, there should be no general ban on international travel or trade, nor any restrictions on the travel of EVD survivors. (1) On 7 November 2015 WHO declared that Ebola virus transmission in Sierra Leone had ended. Forty-two days after the last person confirmed to have Ebola virus disease had a second negative blood test, the country entered a 90-day period of enhanced surveillance. (2) ► (1) WHO Statement, 5 October 2015. (2) WHO News release, 7 November 2015. Measles immunization gap persists G e n e v a – WHO has reported that although an estimated 17.1 million lives have been saved since 2000 through measles vaccination, 2015 global milestones and measles elimination goals are off track. New published data shows that since 2010 overall progress towards increasing global immunization coverage has stagnated at 85% of children having received their first dose of measles vaccination, and only half of the world’s children receiving the recommended second dose. Despite successful implementation of vaccination campaigns in a number of countries, more than 100 000 children needlessly died from measles in 2014. Large outbreaks were reported from China, the Philippines, Viet Nam, Angola, Ethiopia, India, the Russian Federation and Somalia. Such outbreaks happen when there are gaps in vaccination programmes and continue to pose a serious challenge to meeting global targets. ►WHO News release, 12 November 2015. Antiretroviral treatment WHO recommends treatment for all people living with HIV G e n e v a – WHO has published new guidelines recommending that anyone infected with HIV should begin antiretroviral therapy (ART) as soon after diagnosis as possible. The recommendations are supported by recent findings from clinical trials confirming that early use of ART keeps people living with HIV alive, healthier and reduces the risk of transmitting the virus to partners. WHO now also recommends that people at “substantial” risk of HIV should be offered preventive antiretroviral treatment. This should be seen as an additional prevention choice based on a comprehensive package of services, including HIV testing, counselling and support, and access to condoms and safe injection equipment. The new recommendations increase the number of people eligible for ART from 28 million to 37 million people globally. The recommendations were developed as part of a comprehensive update of WHO guidelines on ART. They were published ahead of the full guidelines because of their potential for public health impact. ►WHO News release, 30 September 2015. Updated optimal list of ARVs for children G e n e v a – The Inter-Agency Task Team (IATT) on the Prevention and Treatment of HIV Infection in Pregnant Women, Mothers and Children and other groups is Publications and events WHO Drug Information Vol. 29, No. 4, 2015 478 focused on meeting the needs of children with HIV infection. The IATT has published an update to the Optimal and Limited-Use Paediatric ARV Formularies, for use by governments and implementing agencies. The lists provide guidance on optimal products that are most readily available on the market and comply with WHO treatment guidance. The IATT works with WHO and UNICEF to periodically review and update these formularies. ► IATT. Update to the Optimal List of Paediatric ARV Formulations. Policy brief. Antibiotics International summit on antibiotic resistance U p p s a l a – Following the adoption of the global action plan on antimicrobial resistance by the World Health Assembly in May 2015, some 200 stakeholders and experts from all parts of the world met at the 2015 Uppsala Health Summit in October to engage in dialogue how to put this action plan into practice. The discussions held at the summit are documented in a post-conference report, which calls for information and education, leadership from governments and international organizations, and delinking of peoples’ incomes from antibiotics sales. It was further stressed that rational use requires access to diagnostics and data on resistance, which is lacking particularly in developing countries, and that communication, coordination and more analyses on the consequences of antibiotics resistance are needed, including analyses on the cost of inaction. Research efforts to develop new antibiotics need to be intensified. While academia and small and medium size enterprises were seen as the most appropriate place for the discovery of new antimicrobial compounds, the expertise and experience of the pharmaceutical industry will be important to increase the chance of success. ►Uppsala Health Summit. Conference report points the way in the fight against antibiotic resistance [web page]. 9 October 2015. Use of veterinary antibiotics in Europe E u r o p e a n U n i o n – The EMA has released its fifth report on sales of antibiotics used in animals. According to this report, overall sales in the period 2011-2013 have decreased by approximately 8%, with 11 countries reporting decreases and six countries reporting increases. Sales data on veterinary antibiotics are collected annually as part of the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) project, which is a cooperation between the national authorities throughout the European Union (EU) and is coordinated by EMA. A total of 26 countries from the European Economic Area (EEA) contributed data for the fifth ESVAC report, which comes with an interactive database tool. (1) In November 2015, the EMA released its new strategy on antimicrobials adopted by its Committee for Veterinary Medicinal Products for public consulltation. The strategy recognizes that antimicrobial resistance affects both animal and human health and sets clear objectives to help combat the threat of resistance which may arise from the use of antimicrobials in animals. Comments are invited until 29 February 2016. (2) ► (1) EMA News, 15 October 2015. (2) EMA News, 17 November 2015. 479 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events Multi-country survey reveals misconceptions on antibiotic resistance G e n e v a – A multi-country survey shows that people are confused about antibiotic resistance. Three quarters (76%) of respondents think it happens when the body becomes resistant to antibiotics, 66% believe that they are not at risk if they personally take their antibiotics as prescribed, and 44% think that it is only a problem for people who take antibiotics regularly. In fact, anyone, of any age, in any country can get an infection with bacteria that are resistant to antibiotics. What people can do to address antibiotic resistance is also not well understood. For example, 64% of respondents believe that antibiotics can be used to treat colds and flu, and 32% believe they do not need to complete the prescribed course of treatment if they feel better. More than half (57%) feel there is not much they can do to stop antibiotic resistance, while 64% believe medical experts will solve the problem before it becomes too serious. Another key finding of the survey was that almost three quarters (73%) of respondents said farmers should give fewer antibiotics to food-producing animals. The survey findings coincide with the launch of a new WHO campaign ‘Antibiotics: Handle with care’ – a global initiative to improve understanding of the problem. Antibiotic resistance is one of the biggest health challenges of the 21st century and will require global behaviour change by individuals and societies. ►WHO News release, 16 November 2015. Lists and manuals Indicators to assess pharmacovigilance systems G e n e v a – WHO has published a practical manual for assessment of pharmacovigilance systems, with indicators that can be understood by health care workers without formal training in monitoring and evaluation. The proposed indicators are based on the expected functions of pharmacovigilance centres as described in the WHO’s Minimum Requirements for a Functional Pharmacovigilance System. They reflect the existing structures, the processes used, and the outcomes or impact achieved in pharmacovigilance systems. Pharmacovigilance is critical to monitor the safety and safe use of medicines in public health programmes. The manual proposes a set of nine pharmacovigilance indicators for public health programmes. Pharmacovigilance is also a regulatory function. A subset of indicators from this manual has been included in the WHO harmonized tool for assessing a national regulatory agency (NRA). The manual is published as version 1 (v1.0) to underscore its evolving nature. Feedback from user groups will be used in developing the subsequent versions. ►WHO pharmacovigilance indicators. A practical manual for the assessment of pharmacovigilance systems. Geneva; WHO: 2015. Specifications for selected HIV diagnostics G e n e v a – WHO, in collaboration with a wide range of institutions constituting the technical working group for procurement specifications of HIV diagnostics, has Publications and events WHO Drug Information Vol. 29, No. 4, 2015 480 published its updated technical report to support efficient procurement of essential equipment and laboratory commodities for HIV. This procurement tool covers all laboratory items approved for procurement by WHO and the Global Fund. The manual includes lists of laboratory items required to perform HIV-related tests on specific defined technology, specifications of the items to facilitate their procurement, examples of quantities of reagents required to perform 1000 tests, and price benchmarks that will continue to be updated based on procurement of the contributing partners. This information assists professionals in understanding the different technologies and their cost implications, and in ensuring that all items are ordered in adequate quantities. ►Specifications and quantities for efficient procurement of essential equipment and laboratory commodities for HIV. Second Edition. July 2015. WHO matters WHO launches independent assessment of snake antivenoms G e n e v a – In response to the current crisis in the supply of antivenoms, WHO has decided to offer an independent assessment of antivenoms. A call to manufacturers of antivenoms intended for use in sub-Saharan Africa was sent out in December 2015 (1). About 5 million people are bitten by snakes every year, causing around 125 000 deaths and 400 000 people to be permanently disabled or disfigured. News that one of the most effective treatments for snake bite, Fav-Afrique, will run out in 2016 has caused dismay among public health experts and has spurred media interest in the subject. A prequalification scheme for antivenoms could incentivize manufacturers to develop and produce affordable, good quality antivenoms. Financial backing from donors will be needed to address this issue, on which WHO has attempted to raise the alarm for a number of years. WHO also encourages Just published! CD ROM International Pharmacopoeia Fifth Edition, 2015. CD ROM Quality Assurance of Pharmaceuticals. Update 2015. WHO medicines quality assurance guidelines, good practices documents and training modules. Order online: www.who.int/bookorders 481 WHO Drug Information Vol. 29, No. 4, 2015 Publications and events research to develop new therapeutic options for snakebites. (2) WHO prequalification is open to a range of priority medical products by invitation for expression of interest (3). In November 2015 updated invitations were published for active pharmaceutical ingredients (API), for reproductive health medicines and for medicines to treat HIV infection and related diseases, including treatments for hepatitis B and C. ► (1) WHO Prequalification update, 4 December 2015. ► (2) WHO Prequalification update, 2 October 2015. (3) WHO Prequalification. Invitations for Expressions of Interest (EOIs) [web page]. WHO Expert Committees on medicines meet in Geneva G e n e v a – The WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) held its 50th meeting in Geneva on 12–16 October 2015. The experts adopted a number of monographs and texts for The International Pharmacopoeia as well as new and revised WHO guidelines. Some important new guidance has been adopted. Good pharmacopoeial practices, as recommended by a group of world pharmacopoeias, will support convergence and could reduce the costs caused by differences among standards. In collaboration with the International Pharmaceutical Federation (FIP), guidance has been developed on points to consider in the preparation of children- specific medicines that are not available as authorized products. New guidance has also been adopted on regulatory control of variations and on conducting medicines quality surveys. The finalized guidelines will be published as annexes to the WHO Technical Report Series in 2016. The working versions are available on the WHO web site. The WHO Expert Committees on Biological Standardization and on the Selection and Use of Essential Medicines, as well as the International Nonproprietary Names (INN) Expert Group, met concurrently with the ECSPP and provided their updates and input on some cross- cutting issues. ►WHO Essential medicines and health products. 50th Expert Committee on Specifications for Pharmaceutical Preparations [web page]. New web site on substandard and falsified medicines Geneva – WHO has launched a new website on substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC) medical products, with answers to frequently asked questions and links to related information and WHO activities, such as the global WHO surveillance and monitoring system. The existence of SSFFC products is an unacceptable risk to public health. They affect every region of the world, harm patients and undermine confidence in medical products, healthcare professionals and health systems. SSFFC products from every category have been reported. WHO is working with stakeholders to minimize the risks from SSFFC medical products by collecting data and transferring knowledge and good practices to countries. ►WHO Essential Medicines and health products. Substandard, Spurious, Falsely labelled, Falsified and Counterfeit (SSFFC) Medical Products [web site]. æ 482 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents To receive draft monographs by email please contact Mrs Wendy Bonny (bonnyw@who.int), specifying that you wish to be added to the electronic mailing list. The International Pharmacopoeia Cycloserine (Cycloserinum) This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.638, August 2015). The working document with line numbers and tracked changes is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int. [Note from the Secretariat. Following up on information received from a customer of The International Pharmacopoeia it is proposed to revise the monograph on Cycloserine.] [Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.] C3H6N2O2 Relative molecular mass. 102.1. Chemical name. (4R)-4-aminoisoxazolidin-3-one; (4R)-4-amino-1,2-oxazolidin-3-one; (+)-4-amino-3-isoxazolidinone; CAS Reg. No. 68-41-7. Description. A white or pale yellow, crystalline, powder. Solubility. Freely soluble in water; slightly soluble in methanol R and propylene glycol R; very slightly soluble in ethanol (~750 g/L) TS; practically insoluble in dichloromethane R. Category. Antibacterial drug; antituberculosis drug. Storage. Cycloserine should be kept in a tightly closed container. 483 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents Additional information. Cycloserine is slightly hygroscopic and degrades upon exposure to a humid atmosphere, decomposition being faster at higher temperatures. Requirements Definition. Cycloserine is an analogue of the amino acid D-alanine with broad-spectrum antibiotic and glycinergic activities produced by Streptomyces garyphalus and Streptomyces orchidaceus or obtained by synthesis. Cycloserine contains not less than 98.5% and not more than 101.5% of cycloserine (C3H6N2O2), calculated with reference to the dried substance. Identity tests • Either tests A and C, or tests B and C, or test D alone may be applied. A. Carry out test A.1 or, where UV detection is not available, test A.2. A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R6 as the coating substance and a mixture of 4 volumes of 1-butanol R, 1 volume of glacial acetic acid R and 2 volumes of water R as the mobile phase. Apply separately to the plate 10 µL of each of the following two solutions. For solution (A) dissolve 20 mg of the test substance in 0.5 mL of water R, add 4.5 mL of methanol R and shake. For solution (B) use 20 mg of cycloserine RS prepared in the same manner. After removing the plate from the chromatographic chamber allow it to dry exhaustively in a current of air. Examine the chromatogram in ultraviolet light (254 nm). The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B). A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using the conditions described above under test A.1, but using silica gel R5 as the coating substance. After removing the plate from the chromatographic chamber allow it to dry in a current of air and place the plate in a chamber with iodine vapours. Examine the chromatogram in daylight. The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B). B. Dissolve about 1 mg in 10 mL of sodium hydroxide (0.1 mol/L) VS. To 1 mL of the resulting solution add 3 mL of acetic acid (~60 g/L) TS and 1 mL of a recently prepared mixture of equal volumes of a 40 mg/mL solution of sodium nitroprusside R and sodium hydroxide (~200 g/L) TS; a blue colour gradually develops. C. The absorption spectrum (1.6) of a freshly prepared 25 μg/mL solution in hydrochloric acid (0.1mol/L) VS, when observed between 215 nm and 360 nm, exhibits a maximum at about 219 nm; the specific absorbance ( ) is between 327 and 361. D. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from cycloserine RS or with the reference spectrum of cycloserine. Specific optical rotation (1.4). Use a 50 mg/mL solution in sodium hydroxide (~80 g/l) TS and calculate with reference to the dried substance; = +108° to +114°. Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 484 Heavy metals. Use 2.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 µg/g. Sulfated ash (2.3). Not more than 5.0 mg/g. Loss on drying. Dry at 60°C under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) for 3 hours; it loses not more than 10 mg/g. pH value (1.13). pH of a 100 mg/mL solution in carbon-dioxide-free water R, 5.5 to 6.5. Related substances Prepare fresh solutions and perform the tests without delay. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm) packed with base deactivated particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm). The mobile phases for gradient elution consist of a mixture of mobile phase A and mobile phase B using the following conditions: Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of 0.02 mol/L sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes of water R. Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of 0.02 mol/L sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes of water R. Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodium octanesulfonate R in 1000 mL of water R. Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogen phosphate R in 800 mL of water R, adjust the pH to 2.8 by adding phosphoric acid (~20 g/L) TS and dilute to 1000 mL with water R. Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments 0–16 100 0 Isocratic 16–18 100 to 0 0 to 100 Linear gradient 18–22 0 100 Isocratic 22–24 0 to 100 100 to 0 Return to initial composition 24–30 100 0 Re-equilibration Prepare the following solutions in mobile phase A. For solution (1) use a solution containing 1.0 mg of the test substance per mL. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 5.0 μg of cycloserine per mL. For solution (3) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 25 μg of cycloserine per mL. Heat carefully in a boiling water-bath for 30 minutes. For solution (4) use a solution containing 2.0 µg of D-serine R per mL. Operate with a flow rate of 1.0 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 195 nm. Maintain the column temperature at 45°C. 485 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents Inject 50 μL of solution (3). The test is not valid unless the resolution between the principal peak corresponding to cycloserine (retention time about 14 min) and the large degradation peak with a relative retention time of about 0.23 is not less than 20. Inject alternately 50 μL each of solutions (1), (2) and (4). In the chromatogram obtained with solution (1) the following impurities, if present, are eluted at the following relative retention with reference to cycloserine (retention time about 14 minutes): impurity B (D-serine) about 0.23, impurity C about 0.35 and impurity A about 1.8. In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity B (D-serine) is not greater than the area of the principal peak in the chromatogram obtained with solution (4) (0.2%); • the area of any other peak, other than the principal peak, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%); • the sum of the areas of all peaks, other than the principal peak and any peak corresponding to impurity B (D-serine), is not greater than three times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%). Assay Dissolve about 0.1 g, accurately weighed, in 5 mL of water R. Add 75 mL of 2-propanol R and titrate with carbonate-free sodium hydroxide (0.1 mol/L) VS using thymolphthalein/ ethanol TS as indicator. Perform a blank determination and make any necessary correction. Each mL of sodium hydroxide (0.1 mol/L) VS is equivalent to 10.21 mg of C3H6N2O2. Impurities A. (3R,6R)-3,6-bis[(aminooxy)methyl]piperazine-2,5-dione (cycloserine dimer), B. (2R)-2-amino-3-hydroxypropanoic acid (D-serine), C. condensation product with unknown structure. *** Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 486 Cycloserine capsules (Cycloserini capsulae) This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.637, August 2015). The working document with line numbers and tracked changes is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int. [Note from the Secretariat. Following up on information received from a customer of The International Pharmacopoeia it is proposed to revise the monograph on Cycloserine capsules.] [Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.] Category. Antibacterial drug; antituberculosis drug. Storage. Cycloserine capsules should be kept in a tightly closed container. Additional information. Strength in the current WHO Model List of Essential Medicines (EML): 250 mg. Strength in the current EML for children: 250 mg. Requirements Comply with the monograph for Capsules. Definition. Cycloserine capsules contain Cycloserine. They contain not less than 90.0% and not more than 110.0% of the amount of cycloserine (C3H6N2O2) stated on the label. Manufacture. The manufacturing process and the product packaging are designed and controlled so as to minimize the moisture content of the capsules. They ensure that, if tested, the contents of the capsules would comply with a loss on drying limit of not more than 20 mg/g when determined by drying a suitable quantity of the contents of the capsules for 3 hours under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) at 60°C. Identity tests • Either tests A and B or tests B and C may be applied. A. Carry out test A.1 or, where UV detection is not available, test A.2. A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R6 as the coating substance and a mixture of 4 volumes of 1-butanol R, 1 volume of glacial acetic acid R and 2 volumes of water R as the mobile phase. Apply separately to the plate 10 µL of each of the following two solutions. For solution (A) shake a quantity of the contents of the capsules equivalent to 40 mg of cycloserine with 1 mL of water R, add 9 mL of methanol R, shake again, filter and use the filtrate. For solution (B) dissolve 20 mg of cycloserine RS in 0.5 mL of water R, add 4.5 mL of methanol R and shake. After removing the plate from the chromatographic chamber allow it to dry exhaustively in a current of air. Examine the chromatogram in ultraviolet light (254 nm). 487 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents The principal spot obtained with solution A corresponds in position, appearance and intensity with that obtained with solution B. A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using the conditions described above under test A.1, but using silica gel R5 as the coating substance. After removing the plate from the chromatographic chamber allow it to dry in a current of air and place the plate in a chamber with iodine vapours. Examine the chromatogram in daylight. The principal spot obtained with solution A corresponds in position, appearance and intensity with that obtained with solution B. B. Shake a quantity of the contents of the capsules containing 10 mg of cycloserine with 100 mL of sodium hydroxide (~40 g/L) TS and filter. To 1 mL of the filtrate add 3 mL of acetic acid (~60 g/L) TS and 1 mL of a recently prepared mixture of equal volumes of a 40 mg/mL solution of sodium nitroprusside R and sodium hydroxide (~200 g/L) TS; a blue colour gradually develops. C. See the test described under “Assay”, Method A. The retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that in the chromatogram obtained with solution (2). Related substances Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Assay”, Method A. Prepare the following solutions in mobile phase A. For solution (1) transfer a quantity of the contents of the capsules containing 100 mg of cycloserine into a 100 mL volumetric flask. Add about 70 mL, shake for 5 minutes, make up to volume and filter. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration containing 5.0 μg of cycloserine per mL. For solution (3) dilute a suitable volume of solution (1) to obtain a concentration of 25 µg of cycloserine per mL. Heat carefully in a boiling water-bath for 30 minutes. For solution (4) use a solution containing 2.0 µg of D-serine R per mL. Inject 50 μL of solution (3). The test is not valid unless the resolution between the principal peak corresponding to cycloserine (retention time about 14 minutes) and the large degradation peak with a relative retention time of about 0.23 is not less than 20. Inject alternately 50 μL each of solutions (1), (2) and (4). In the chromatogram obtained with solution (1) the following impurities, if present, are eluted at the following relative retention with reference to cycloserine (retention time about 14 minutes): impurity B (D-serine) about 0.23, impurity C about 0.35 and impurity A about 1.8. In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity B (D-serine) is not greater than twice the area of the principal peak in the chromatogram obtained with solution (4) (0.4%); • the area of any other peak, other than the principal peak, is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (1.0%); • the sum of the areas of all peaks, other than the principal peak and any peak corresponding to impurity B (D-serine), is not greater than six times the area of the principal peak in the chromatogram obtained with solution (2) (3.0%). Disregard any peak with an area less than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%). Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 488 Assay • Either method A or method B may be applied. A. Carry out the assay as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm) packed with base deactivated particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 μm). The mobile phases for gradient elution consist of a mixture of Mobile phase A and Mobile phase B, using the following conditions: Mobile phase A: 4 volumes of acetonitrile R, 70 volumes of a 0.02 mol/L sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 16 volumes of water R. Mobile phase B: 17 volumes of acetonitrile R, 70 volumes of a 0.02 mol/L sodium octanesulfonate R solution, 10 volumes of phosphate buffer pH 2.8 and 3 volumes of water R. Prepare the sodium octanesulfonate solution by dissolving 4.7 g of sodium octanesulfonate R in 1000 mL of water R. Prepare the phosphate buffer pH 2.8 by dissolving 27.2 g of potassium dihydrogen phosphate R in 800 mL of water R, adjust the pH to 2.8 by adding phosphoric acid (~20 g/L) TS and dilute to 1000 mL with water R. Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments 0–16 100 0 Isocratic 16–18 100 to 0 0 to 100 Linear gradient 18–22 0 100 Isocratic 22–24 0 to 100 100 to 0 Return to initial composition 24–30 100 0 Re-equilibration Prepare the following three solutions in mobile phase A. For solution (1) weigh and mix the contents of 20 capsules and transfer a quantity of the contents containing about 10 mg of cycloserine, accurately weighed, into a 100 mL volumetric flask. Add about 70 mL, shake for 5 minutes, make up to volume and filter. For solution (2) use 0.1 mg of cycloserine RS per mL. For solution (3) dilute a suitable volume of solution (1) to obtain a concentration of 25 μg of cycloserine per mL. Heat carefully in a boiling water-bath for 30 minutes. Operate with a flow rate of 1.0 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 195 nm. Maintain the column temperature at 45°C. Inject 50 μL of solution (3). The test is not valid unless the resolution between the principal peak corresponding to cycloserine (retention time about 14 minutes) and the large degradation peak with a relative retention time of about 0.23 is not less than 20. Inject alternately 50 µL each of solutions (1) and (2). 489 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents Measure the areas of the peaks responses obtained in the chromatograms from solutions (1) and (2) and calculate the content of cycloserine (C3H6N2O2) in the capsules, using the declared content of C3H6N2O2 in cycloserine RS. B. Weigh and mix the contents of 20 capsules and transfer a quantity of the contents containing 0.250 g of cycloserine, accurately weighed, into a 200 mL volumetric flask. Add hydrochloric acid (0.1mol/L) VS to volume, shake for 10 minutes and filter. Dilute 2 mL of the filtrate to 100 mL with hydrochloric acid (0.1mol/L) VS. Measure the absorbance (1.6) of this solution in a 1 cm layer at the maximum at about 219 nm against a solvent cell containing hydrochloric acid (0.1mol/L) VS. Calculate the content of cycloserine (C3H6N2O2) in the capsules, using an absorptivity value of 34.3 ( = 343). Impurities The impurities limited by the requirements of this monograph include those listed in the monograph for Cycloserine. *** Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 490 Ceftriaxone sodium (Ceftriaxonum natricum) This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.644, November 2015). The working document with line numbers is available for comment at www.who. int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int. C18H16N8Na2O7S3,3½H2O Relative molecular mass. 661.60 Chemical name. Disodium (6R,7R)-7-[[(2Z)-(2-aminothiazol-4-yl)(methoxyimino) acetyl] amino]-3-[[(2-methyl-6-oxido-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulfanyl]meth- yl]-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 3.5 hydrate. Description. Almost white or yellowish, slightly hygroscopic, crystalline powder. Solubility. Freely soluble in water, sparingly soluble in methanol, very slightly soluble in anhydrous ethanol. Labelling. The label states, where applicable: • that the substance is free of bacterial endotoxins; • that the substance is sterile. Category. Antibacterial Storage. Ceftriaxone sodium should be kept in an air-tight container protected from light. If the substance is sterile, store in a sterile and air-tight container protected from light. Requirements Ceftriaxone sodium contains not less than 96.0% and not more than 102.0% of the labelled amount of ceftriaxone sodium (C18H16N8Na2O7S3), calculated with reference to the anhydrous substance. Identity tests • Either tests A and C or tests B and C may be applied. A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from ceftriaxone sodium RS or with the reference spectrum of ceftriaxone sodium. 491 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents B. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under the Assay test. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to the retention time of the peak corresponding to ceftriaxone in the chromatogram obtained with solution (2). C. When tested for sodium as described under 2.1 General identification tests, yields the characteristic reaction. Specific optical rotation (1.4). Dissolve 0.250 g in water R and dilute to 25.0 mL with the same solvent. Calculate with reference to the anhydrous substance; = –155° to –170°. Clarity and colour of solution. Dissolve 2.40 g in carbon-dioxide-free water R and dilute to 20.0 mL with the same solvent (Solution A). Dilute 2 mL of Solution A to 20 mL carbon-dioxide- free water R. The solution is clear and not more intensely coloured than reference solution YW2 when compared as described under 1.11 Colour of liquids. (Keep the remaining solution (Solution A) for the “pH value”.) pH value (1.13). pH of the solution prepared for the “Clarity and colour of solution” (Solution A), 6.0 to 8.0. Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, method A, using about 0.1 g of the test substance. The water content is not less than 80 mg per g and not more than 110 mg per g. Bacterial endotoxins. If intended for use in the manufacture of a parenteral dosage form without a further appropriate procedure for the removal of bacterial endotoxins, carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 0.20 IU of endotoxin per mg of ceftriaxone sodium. Related substances Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given below under assay method. Prepare the following solutions in mobile phase: for solution (1) dissolve about 30 mg of the test substance and dilute to 100.0 mL. For solution (2) dilute 1 volume of solution (1) to 100 volumes. For solution (3) dissolve about 5 mg ceftriaxone sodium RS and 5 mg of ceftriaxone impurity G to 100.0 mL. Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the peaks due to ceftriaxone and ceftriaxone impurity G is at least 3.0. Ceftriaxone impurity G is eluted at a relative retention of 1.4 with reference to ceftriaxone (retention time about 9 min). Inject alternately 20 µL each of solution (1) and (2). Record the chromatograms for about 2 times the retention time of ceftriaxone. The chromatogram obtained with solution (1) may show the following impurities at the following relative retention with reference to ceftriaxone: impurity A: about 0.2; impurity B: about 0.34; impurity C: about 0.62; impurity D: about 0.72; impurity E: about 0.78; impurity F: about 1.3 and impurity G: about 1.4. In the chromatogram obtained with solution (1): • the area of any peak, other than the principal peak, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0 %); • the sum of the areas of all peaks, other than the principal peak, is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (2.5 %). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%). Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 492 Assay Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm) packed with particles of base-deactivated silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm) 1. As the mobile phase use a solution prepared as follows: dissolve 2.0 g of tetradecylammonium bromide R and 2.0 g of tetraheptylammonium bromide R in a mixture of 440 mL of water R, 55 mL of phosphate buffer pH 7.0 (0.067 mol/L) TS , 5.0 mL of citrate buffer pH 5.0 TS and 500 mL of acetonitrile R and filter. Prepare the following solutions in mobile phase. For solution (1) dissolve 30 mg of the test substance, accurately weighed and dilute to 100.0 mL. For solution (2) dissolve about 30 mg of ceftriaxone sodium RS, accurately weighed and dilute to 100.0 mL. For solution (3) dissolve about 5 mg ceftriaxone sodium RS and about 5 mg of ceftriaxone impurity G and dilute to 100.0 mL. Operate with a flow rate of 1.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 254 nm. Inject 20 µL of solution (3).The test is not valid unless the resolution factor between the peaks due to ceftriaxone and ceftriaxone impurity G is at least 3.0. Inject alternately 20 µL each of solution (1) and (2). Measure the areas of the peaks corresponding to ceftriaxone and calculate the percentage content of ceftriaxone sodium (C18H16N8Na2O7S3) with reference to the anhydrous substance. Sterility. If intended for use in the manufacture of a parenteral dosage form without a further appropriate sterilization procedure, complies with 3.2 Test for sterility. Impurities [Note from the Secretariat. The structures of the impurities will be added at a later stage.] A. (Z)-2-(2-Aminothiazol-4-yl)-N-{(5aR,6R)-1,7-dioxo-1,3,4,5a,6,7-hexahydroazeto[2,1-b] furo[3,4-d][1,3]thiazin-6-yl}-2-(methoxyimino)acetamide. (Deacetylcefotaxime lactone) B. (6R,7R)-3-(Acetoxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. (7-Aminocephalosporanic acid) C. 3-Mercapto-2-methyl-1,2-dihydro-1,2,4-triazine-5,6-dione. (Ceftriaxone triazine analog) D. (Z)-S-Benzothiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)thioacetate (Ceftriaxone benzothiazolyl oxime). E. (6R,7R)-7-Amino-3-{[(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio]methyl}- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Deacyl ceftriaxone). F. (6R,7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-{[(6-hydroxy-2- methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-3-ene-2-carboxylic acid (Ceftriaxone 3-ene isomer). G. (6R,7R)-7-[(E)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-{[(6-hydroxy-2- methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid (Ceftriaxone E-isomer). Reagent to be included: Citrate buffer, pH 5 TS Procedure. Dissolve 20.17 g of citric acid R in 800 ml of water R, adjust to pH 5.0 with sodium hydroxide (~400 g/L) TS and dilute to 1000 mL with water R. *** 1 Hypersil BDS C18 has been found suitable. 493 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents Ceftriaxone for injection (Ceftriaxoni ad injectionem) This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.645, November 2015). The working document with line numbers is available for comment at www.who. int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int. Description. A white and almost white powder. Category. Antibacterial. Storage. Ceftriaxone for injection should be stored in a tightly closed container. The reconstituted solution should be used immediately after preparation. Additional information. Strengths in the current WHO Model List of Essential Medicines (EML): 250 mg, 1 g (as sodium salt) in vial. Strength in the current WHO EML for children: 250 mg, 1 g (as sodium salt) in vial. Requirements The powder for injection and the reconstituted solution for injections comply with the monograph on Parenteral preparations. Definition. Ceftriaxone for injection is a sterile powder containing Ceftriaxone sodium with or without excipients. Ceftriaxone for injection contains not less than 90.0% and not more than 110.0% of the labelled amount of ceftriaxone (C18H18N8O7S3). Identity tests • Either tests A and C or tests B and C may be applied. A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from ceftriaxone sodium RS or with the reference spectrum of ceftriaxone sodium. B. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Assay”. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to the retention time of the ceftriaxone peak in the chromatogram obtained with solution (2). C. When tested for sodium as described under 2.1 General identification tests, yields the characteristic reaction. Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, method A, using about 0.1 g of the powder. The water content is not more than 110 mg per g. Consultation documents WHO Drug Information Vol. 29, No. 4, 2015 494 Clarity and colour of solution. Dissolve 2.40 g in carbon-dioxide-free water R and dilute to 20.0 mL with the same solvent (Solution A). Dilute 2 mL of Solution A to 20 mL carbon-dioxide- free water R. The solution is clear and not more intensely coloured than reference solution YW2 when compared as described under 1.11 Colour of liquids. (Keep the remaining solution (Solution A) for the “pH value”.) pH value (1.13). pH of the solution prepared for the “Clarity and colour of solution” (Solution A), 6.0 to 8.0. Bacterial endotoxins. Carry out the test described under 3.4 Test for bacterial endotoxins, contains not more than 0.19 IU of endotoxin per mg of ceftriaxone. Related substances Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given below under assay method. Prepare the following solutions in mobile phase: for solution (1) dissolve about 30 mg of the powder and dilute to 100.0 mL. For solution (2) dilute 1 volume of solution (1) to 100 volumes. For solution (3) dissolve about 5 mg ceftriaxone sodium RS and 5 mg of ceftriaxone impurity G to 100.0 mL. Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the peaks due to ceftriaxone and ceftriaxone impurity G is at least 3.0. Ceftriaxone impurity G is eluted at a relative retention of 1.4 with reference to ceftriaxone (retention time about 9 min). Inject alternately 20 μL each of solutions (1) and (2). Record the chromatograms for about 2 times the retention time of ceftriaxone. The chromatogram obtained with solution (1) may show the following impurities at the following relative retention with reference to ceftriaxone: impurity A: about 0.2; impurity C: about 0.62; impurity D: about 0.72; impurity E: about 0.78; impurity F: about 1.3 and impurity G: 1.4. In the chromatogram obtained with solution (1) • the area of any peak, other than the principal peak, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0 %); • the sum of the areas of all peaks, other than the principal peak, is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (2.5%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%). Assay Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm) packed with particles of base-deactivated silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm) 2. As the mobile phase use a solution prepared as follows: dissolve 2.0 g of tetradecylammonium bromide R and 2.0 g of tetraheptylammonium bromide R in a mixture of 440 mL of water R, 55 ml of phosphate buffer, pH 7.0 (0.067 mol/L) TS, 5.0 mL of a citrate buffer pH 5.0 TS and 500 mL of acetonitrile R and filter. 2 Hypersil BDS C18 has been found suitable. 495 WHO Drug Information Vol. 29, No. 4, 2015 Consultation documents Prepare the following solutions in mobile phase: for solution (1) determine the weight of the contents of 10 containers. Transfer a quantity of the mixed contents containing about 30 mg of ceftriaxone, accurately weighed, to a 100 mL volumetric flask, dissolve and dilute to volume. For solution (2) dissolve about 35 mg of ceftriaxone sodium RS, accurately weighed and dilute to 100.0 mL. For solution (3) dissolve about 5 mg ceftriaxone sodium RS and 5 mg of ceftriaxone impurity G to 100.0 mL. Operate with a flow rate of 1.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 254 nm. Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the peaks due to ceftriaxone and ceftriaxone impurity G is at least 3.0. Inject 20 µL of solution (1) and (2) Measure the areas of the peaks corresponding to ceftriaxone and calculate the content of ceftriaxone (C18H18N8O7S3) per container. Each mg of C18H16N8Na2O7S3 is equivalent to 0.9274 mg of C18H18N8O7S3. Impurities The impurities limited by the requirements of this monograph include those listed in the monograph for Ceftriaxone sodium. *** ATC/DDD classification WHO Drug Information Vol. 29, No. 4, 2015 496 ATC/DDD classification The Anatomical Therapeutic Chemical (ATC) classification system and the Defined Daily Dose (DDD) as a measuring unit are tools for exchanging and comparing data on drug use at international, national or local levels. The ATC/DDD system has become the gold standard for international drug utilization research. It is maintained by the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway. Visit www.whocc.no/ for more information. ATC/DDD classification (temporary) The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in October 2015. Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 February 2016. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2017 version of the ATC/DDD Index. New ATC 5th level codes: Please note that the list does not include new ATC codes established as a result of ATC alterations. ATC level name/INN ATC code aceneuramic acid M09AX05 alectinib L01XE36 alirocumab C10AX14 aminobenzoate potassium D11AX23 arterolane and piperaquine P01BX02 carvedilol and ivabradine C07FX06 cobimetinib L01XE38 daratumumab L01XC24 deoxycholic acid D11AX24 desfesoterodine G04BD13 edoxaban B01AF03 elbasvir and grazoprevir J05AX68 elotuzumab L01XC23 eluxadoline A07DA06 empegfilgrastim L03AA16 etelcalcetide H05BX04 ferric maltol B03AB10 fluoroethyl-L-tyrosine (18F) V09IX10 follitropin delta G03GA10 /Continued 497 WHO Drug Information Vol. 29, No. 4, 2015 ATC/DDD classification New ATC 5th level codes, continued ATC level name/INN ATC code gallium (68Ga) endotreotide V09IX09 inotuzumab ozogamicin L01XC26 ixekizumab L04AC13 landiolol C07AB14 metoprolol and ivabradine C07FX05 metreleptin A16AA07 mogamulizumab L01XC25 osimertinib L01XE35 phenylephrine and ketorolac S01FB51 rociletinib L01XE37 safinamide N04BD03 salbutamol and beclometasone R03AK13 talimogene laherparepvec L01XX51 tiazotic acid C01EB23 tramadol and dexketoprofen N02AJ14 trientine A16AX12 New ATC level codes (other than 5th levels): ATC level name ATC code Beta blocking agents, other combinations C07FX Glucagon-like peptide-1 receptor (GLP-1) analogues A10BJ Opioids in combination with non-opioid analgesics N02AJ Sodium-glucose co-transporter 2 (SGLT2) inhibitors A10BK Change of ATC codes: ATC level name/INN Previous ATC code New ATC code albiglutide A10BX13 A10BJ04 canagliflozin A10BX11 A10BK02 dapagliflozin A10BX09 A10BK01 dulaglutide A10BX14 A10BJ05 empagliflozin A10BX12 A10BK03 exenatide A10BX04 A10BJ01 liraglutide A10BX07 A10BJ02 lixisenatide A10BX10 A10BJ03 mepolizumab L04AC06 R03DX09 methotrexate 1) L01BA01 L04AX03 1) nonacog alfa B02BD09 B02BD04 2) tiopronin R05CB12 G04BX16 trenonacog alfa B02BD12 B02BD04 2) 1) Splitting of ATC code. Only the classification of pre-filled syringes of methotrexate for use in non-cancer indications is changed. These products will be moved to the existing ATC code for oral administered product of methotrexate. Parenteral preparations used for treatment of cancer will remain in L01BA01. 2) Existing ATC code B02BD04 coagulation factor IX ATC/DDD classification WHO Drug Information Vol. 29, No. 4, 2015 498 Change of ATC level names: Previous New ATC code atenolol and other antihypertensives atenolol and nifedipine C07FB03 Beta blocking agents and other antihypertensives Beta blocking agents, other combinations C07F Beta blocking agents, selective, and other antihypertensives Beta blocking agents and calcium channel blockers C07FB bisoprolol and other antihypertensives bisoprolol and amlodipine C07FB07 nebivolol and other antihypertensives nevibolol and amlodipine C07FB12 oxycodone, combination oxycodone and naloxone N02AA55 Change of ATC code and/or ATC level name based on new ATC 4th levels established Previous ATC code and level name New ATC code and/or level name C07FA Beta blocking agents, non-selective, and other antihypertensives Deleted C07FX Beta blocking agents, other combinations C07FA05 propranolol and other antihypertensives C07FX01 propranolol and other combinations C07AA57 sotalol, combinations C07FX02 sotalol and acetylsalicylic acid C07AB52 metoprolol, combinations C07FX03 metoprolol and acetylsalicylic acid C07FB02 1) metoprolol and other antihypertensives C07FB02 C07FB13 metoprolol and felodipine 2) metoprolol and amlodipine C07AB57 bisoprolol, combinations C07FX04 bisoprolol and acetylsalicylic acid N02AJ Opioids in combination with non-opioid analgesics N02AA58 3) N02BE51 3) dihydrocodeine, combinations paracetamol, combinations excl. psycholeptics N02AJ01 4) dihydrocodeine and paracetamol N02AA58 3) N02BA51 3) dihydrocodeine, combinations acetylsalicylic acid, combinations excl. psycholeptics N02AJ02 4) dihydrocodeine and acetylsalicylic acid N02AA58 3) dihydrocodeine, combinations N02AJ03 4) dihydrocodeine and other non- opioid analgesics N02AA59 3) N02BE51 3) codeine, combinations excl. psycholeptics paracetamol, combinations excl. psycholeptics N02AJ06 4) codeine and paracetamol /Continued 499 WHO Drug Information Vol. 29, No. 4, 2015 ATC/DDD classification Change of ATC code and/or ATC level name based on new ATC 4th levels established, continued/ Previous ATC code and level name New ATC code and/or level name N02AA59 3) N02BA51 3) codeine, combinations excl. psycholeptics acetylsalicylic acid, combinations excl. psycholeptics N02AJ07 4) codeine and acetylsalicylic acid N02AA59 3) M01AE51 3) codeine, combinations excl. psycholeptics ibuprofen, combinations N02AJ08 4) codeine and ibuprofen N02AA59 3) codeine, combinations excl. psycholeptics N02AJ09 4) codeine and other non-opioid analgesics N02AX52 tramadol, combinations N02AJ13 tramadol and paracetamol N02AA55 3) N02BE51 3) oxycodone, combinations 5) paracetamol, combinations excl. psycholeptics N02AJ17 4) oxycodone and paracetamol N02AA55 3) N02BA51 3) oxycodone, combinations 3) acetylsalicylic acid, combinations excl. psycholeptics N02AJ18 4) oxycodone and acetylsalicylic acid N02AA553) oxycodone, combinations 3) N02AJ19 4) oxycodone and ibuprofen 1) Splitting of ATC code in connection with alterations in C07FX 2) Existing ATC code 3) Splitting of ATC codes according to contents of the different fixed combinations of opioids and other analgesics. The ATC codes in N02AA, N02BA51, N02BE51 and M01AE51 will be maintained for other combinations. 4) Combinations with opioids and other analgesics currently classified in the following ATC codes N02AA55, N02AA58, N02AA59 will be moved to the new ATC 4th level N02AJ. All the existing combination codes will be kept in N02AA since there may be other combinations without analgesics available (e.g. oxycodone and naloxone will remain in N02AA55). The ATC classification of all low dose combinations products of codeine or dihydrocodeine (<20 mg dose) currently classified in N02B or M01A will be altered to the new ATC codes in N02AJ. 5) Combinations of oxycodone and naloxone will be maintained in N02AA55. ATC/DDD classification WHO Drug Information Vol. 29, No. 4, 2015 500 New DDDs: ATC level name/INN DDD unit Adm.R* ATC code alirocumab 5.4 mg P C10AX14 apremilast 60 mg O L04AA32 ataluren 2.8 g O M09AX03 calcium acetate 6 g O V03AE07 cangrelor 50 mg P B01AC25 defibrotide 1.75 g P B01AX01 edoxaban 60 mg O B01AF03 elosulfase alfa 20 mg P A16AB12 evolocumab 14 mg P C10AX13 ferric citrate 6 g O V03AE08 furazidin 0.3 g O J01XE03 iloperidone 18 mg O N05AX14 insulin degludec and liraglutide 40 U 1) P A10AE56 mifepristone, combinations 0.2 g 2) O G03XB51 naloxegol 25 mg O A06AH03 rifapentine 0.11 g O J04AB05 safinamide 75 mg O N04BD03 secukinumab 10 mg P L04AC10 tedizolid 0.2 g O,P J01XX11 * Administration Route: O=oral; P=parenteral 1) Refers to insulin degludec 2) Refers to mifepristone Change of DDD: ATC level name/INN Previous DDD New DDD ATC code DDD Unit Adm.R.* DDD Unit Adm.R.* Blood coagulation factors 1) Deleted 1) B02BD mifepristone 0.6 g O 0.2 g O G03XB01 ampicillin and enzyme inhibitor 2 g 2) P 6 g 2) P J01CR01 * Administration Route: O=oral; P=parenteral 1) DDDs for the various blood coagulation factors in all ATC 5th level codes in B02BD are deleted. No new DDDs will be established in B02BD Blood coagulation factors. 2) Refers to ampicillin 501 WHO Drug Information Vol. 29, No. 4, 2015 ATC/DDD classification ATC/DDD classification (final) The following ATC codes, DDDs and alterations were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in March 2015. These are considered as final and will be included in the January 2016 version of the ATC/DDD Index. New ATC 5th level codes: ATC level name/INN ATC code anthrax immunoglobulin J06BB19 armodafinil N06BA13 atorvastatin, amlodipine and perindopril C10BX11 begelomab L04AA35 brexpiprazole N05AX16 brodalumab L04AC12 cediranib L01XE32 ceftazidime, combinations J01DD52 conjugated estrogens and bazedoxifene G03CC07 drisapersen M09AX04 droxidopa C01CA27 dulaglutide A10BX14 emtricitabine, tenofovir alafenamide and rilpivirine J05AR19 ibuprofen R02AX02 idarucizumab V03AB37 ivacaftor and lumacaftor R07AX30 ixazomib L01XX50 lesinurad M04AB05 necitumumab L01XC22 palbociclib L01XE33 pantoprazole, amoxicillin, clarithromycin and metronidazole A02BD11 perindopril and bisoprolol C09BX02 ramucirumab L01XC21 reslizumab R03DX08 salmeterol and budesonide R03AK12 saxagliptin and dapagliflozin A10BD21 selexipag B01AC27 sodium benzoate A16AX11 tivozanib L01XE34 valsartan and lercanidipine C09DB08 valsartan and sacubitril C09DX04 zoledronic acid, calcium and colecalciferol, sequential M05BB08 Change of ATC codes: ATC level name/INN Previous ATC code New ATC code calcium acetate1) A12AA12 V03AE07 ferric citrate B03AB06 V03AE08 1) Previous ATC level name: calcium acetate anhydrous ATC/DDD classification WHO Drug Information Vol. 29, No. 4, 2015 502 New DDDs: ATC level name/INN DDD unit Adm.R* ATC code alogliptin 25 mg O A10BH04 armodafinil 0.15 g O N06BA13 artesunate 0.28 g P P01BE03 clenbuterol 40 mcg O R03CC13 colistin 3 MU Inhal. powder J01XB01 dasabuvir 0.5 g O J05AX16 dulaglutide 0.16 mg P A10BX14 eliglustat 0.168 g O A16AX10 empagliflozin 17.5 mg O A10BX12 teduglutide 5 mg P A16AX08 tofacitinib 10 mg O L04AA29 umeclidinium bromide 55 mcg2 Inhal. powder R03BB07 * Administration Route: O=oral; P=parenteral 2) Refers to umeclidinium, delivered dose Change of DDDs: ATC level name/INN Previous DDD New temporary DDD ATC code DDD unit Adm.R* DDD unit Adm.R* apixaban 5 mg O 10 mg O B01AF02 dabigatran etexilate 0.22 g O 0.3 g O B01AE07 human menopausal gonadotrophin 30 U P 75 U P G03GA02 rivaroxaban 10 mg O 20 mg O B01AF01 * Administration Route: O=oral; P=parenteral æ