WHO Drug Information Vol. 21, No. 2, 2007

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WHO DRUG INFORMATION

VOLUME 2 1• NUMBER 2 • 2007

PROPOSED INN LIST 9 7 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA WHO Drug Information Vol 21, No. 2, 2007 World Health Organization

WHO Drug Information

Contents Safety and Efficacy Issues Eculizumab approved for paroxysmal Entecavir: not for use in HIV/HBV nocturnal haemoglobinuria 115 co-infection 87 Deferasirox: acute renal failure and Access to Medicines cytopenias 87 Neglected tropical diseases 116 Safety of oseltamivir 87 Open access database for neglected Fluticasone: reports of behavioural medicines development 116 changes 88 Quetiapine: pancreatitis and thrombocytopenia 88 Consultation Document Aprotinin: hypersensitivity reactions and renal dysfunction 89 International Pharmacopoeia Metoclopramide in children: extra- Artemether and lumefantrine capsules 118 pyramidal symptoms 90 Magnesium sulfate injection 123 Drug-eluting stents: to be used with Zinc sulfate 124 caution 90 Paediatric zinc sulfate tablets 125 Darbepoetin alfa and epoetin alfa: update Paediatric zinc sulfate oral solution 127 for non-myeloid malignancies 91 Ayurvedic and Chinese medicines: Recent Publications, heavy metals 91 ADHD drugs: cardiovascular and psychi- Information and Events atric events 92 Informed consent for research in resource- Clozapine can impair motility of the entire poor settings 129 GI tract 93 Lessons learned in home management of malaria 129 Developing drug information centres Essential Medicines in India 130 th 15 Model List of Essential Medicines 94 First-in-man clinical trials for high risk th Model List of Essential Medicines, 15 products 130 Edition, revised March 2007 95 Pakistan Pharmacists Society discussion forum 130 New quality assurance compendium 130 Regulatory Action and News Pharmacological management of human Tegaserod: marketing suspension 112 H5N1 infection 131 Pergolide: voluntary withdrawal of products 112 Aliskiren approved for hypertension 113 Proposed International Lapatinib approved for breast cancer 114 Adalimumab approved for Crohn disease114 Nonproprietary Names: Rapid test for meningitis cleared for List 97 133 marketing 114

85 World Health Organization WHO Drug Information Vol 21, No. 2, 2007

Announcement

The 13th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the Swiss Agency for Therapeutic Products (Swissmedic) in collaboration with the World Health Organization

The ICDRA will take place in Berne, Switzerland from 16 to 19 September 2008

Updated information will be provided regularly at: http://www.icdra.ch

http://www.who.int/medicines/icdra/en/index/html

86 WHO Drug Information Vol 21, No. 2, 2007

Safety and Efficacy Issues

Entecavir : not for use in Deferasirox is indicated in the manage- HIV/HBV co-infection ment of chronic iron overload in patients with transfusion-dependent anaemias European Union — The Committee for aged 6 years or older. It is also indicated Medicinal Products for Human Use in the management of chronic iron over- (CHMP) reminds healthcare professionals load in patients with transfusion-depend- that entecavir (Baraclude¨) has not been ent anaemias aged two to five who evaluated for the treatment of patients cannot be adequately treated with with chronic hepatitis B virus (HBV) infec- deferoxamine. tion who are co-infected with the human immunodeficiency virus (HIV) and are not Therapy should be initiated and main- receiving highly active antiretroviral tained by physicians experienced in the therapy (HAART). treatment of chronic iron overload due to blood transfusions. Based on new data, the EMEA advises healthcare professionals that: Cases of acute renal failure (some with fatal outcome) have been reported ¥ Baraclude¨ has not been evaluated in following the post-marketing use of HIV/HBV co-infected patients not deferasirox. For the fatal cases, it is simultaneously receiving effective HIV impossible to completely exclude a treatment. contributory role of deferasirox to the renal impairment The fact that there was ¥ When considering therapy with ente- an improvement after stopping the cavir in an HIV/HBV co-infected patient treatment in most of the cases with non- not receiving HAART, there appears to fatal acute renal failure is suggestive of a be a risk of developing HIV resistance. contributory role. Deferasirox has not ¥ Until reassuring data become available, been studied in patients with renal impair- Baraclude¨ should only be considered ment. in this setting under exceptional circumstances. Reference: Communication from Novartis Pharmaceuticals Canada Inc. on Medeffect at http://www.hc-sc.gc.ca Reference: European Medicines Agency, Public Statement, EMEA/79902/20075. March 2007. Safety of oseltamivir Deferasirox: acute renal European Union — The European Medicines Agency (EMEA) has docu- failure and cytopenias mented new reports of neuropsychiatric Canada — The manufacturer of defera- adverse events occurring with the use of sirox (Exjade¨) has updated the safety oseltamivir (Tamiflu¨) originating from information regarding reports of acute Japan. These cases have been detected renal failure and peripheral blood cyto- through routine safety monitoring. penias.

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The Agency’s Committee for Medicinal the reporter did not see a causal relation- Products for Human Use (CHMP) has ship between the adverse drug reaction monitored closely all adverse drug and salbutamol. Psychiatric effects have reactions reported in connection with the also been reported in association with the use of oseltamivir since it was introduced use of oral corticosteroids and inhaled in the European Union in 2003. budesonide, which raises the possibility of a group effect. The CHMP recommended an update of the product information on neuropsychi- Reference: Fluticasone inhalation and behavioural changes in children. Lareb, atric side effects: “Convulsion, depressed Netherlands Pharmacovigilance Centre, level of consciousness, abnormal behav- January 2007 (www.lareb.nl). iour, hallucinations and delirium have been reported during Tamiflu¨ administration, leading in rare cases to accidental Quetiapine: pancreatitis injury. Patients, especially children and and thrombocytopenia adolescents should be closely monitored Canada — Quetiapine (Seroquel®) is an and their healthcare professional should atypical antipsychotic drug indicated for be contacted immediately if the patient the management of symptoms of schizo- shows any signs of unusual behaviour.” phrenia and the acute management of manic episodes associated with bipolar The EMEA and CHMP will continue to disorder (1). In Canada, quetiapine has closely monitor any emerging safety been marketed since December 1997. information on Tamiflu¨, including neuropsychiatric disorders. If any concerns From 1997 to 2006, Health Canada has emerge, further action will be taken. With received 615 domestic reports of adverse these measures in place, the CHMP reactions suspected of being associated maintains its opinion that the benefits of with the use of quetiapine. Nine reports Tamiflu¨ outweigh its risks when the involved cases of pancreatitis and 11 product is used according to the adopted involved cases of thrombocytopenia. recommendations. Neither of these ARs is mentioned in the Canadian product monograph (1). Reference: EMEA Press Release, 23 March 2007. Doc. Ref. EMEA/134566/2007. http:// www.emea.europa.eu Pancreatitis The 9 reported cases of pancreatitis involved patients aged 24Ð71 years. In 5 Fluticasone: reports of cases, quetiapine was the only suspect behavioural changes drug; in the other cases, reported co- Netherlands — The Netherlands Phar- suspect drugs included medications that have been associated with pancreatitis: macovigilance Centre, Lareb, has received 17 reports of behavioural changes clozapine, divalproex sodium, fenofibrate in children associated with the use of and minocycline (2, 3). inhaled fluticasone propionate or salmeterol/fluticasone propionate (4). In Acute pancreatitis typically presents as 11 cases, symptoms disappeared when an acute inflammation of the pancreas that may or may not involve the surround- fluticasone propionate was withdrawn. A positive rechallenge was observed in one ing tissues (2). Gallstones and heavy case. Six patients who had received alcohol use are the most common causes (2). The severity of drug-induced pan- fluticasone propionate also received salbutamol. However, in all but one case, creatitis is variable; the majority of pa-

88 WHO Drug Information Vol 21, No. 2, 2007 Safety and Efficacy Issues

tients recover without any long-term 4. Kale-Pradhan PB, Conroy JL. Pancreatitis. morbidity, but 5% Ð15% of patients In: Drug-induced diseases: prevention, experience life-threatening complications detection, and management. Bethesda (MD): (4). People at risk of drug-induced pan- American Society of Health-System Pharma- creatitis include elderly patients taking cists, Inc.; 2005. p. 537Ð47. multiple medications, patients who are 5. Adverse Drug Reactions Advisory Commit- HIV positive, patients who have cancer tee (ADRAC). Drug induced pancreatitis. Aust and patients receiving immunomodulatory Adv Drug Reactions Bull, 2006;25(6):22. agents (5). 6. Skirvin JA. Thrombocytopenia. In: Tisdale Thrombocytopenia JE, Miller DA, editors. Drug-induced diseases: The 11 reported cases of thrombocytope- prevention, detection, and management. nia involved patients aged 28Ð84 years. Bethesda (MD): American Society of Health- In 6 cases, quetiapine was the only System Pharmacists, Inc.; 2005. p. 649Ð59. suspect drug. In 5 cases, reported co- suspect drugs included medications that 7. Kentos A, Robin V, Lambermont M, et al. Probable rofecoxib-induced thrombocytope- have been associated with thrombocyto- nia. Rheumatology, 2003;42(5):699Ð700. penia: citalopram, clozapine, olanzapine, pantoprazole, rofecoxib and zuclopen- 8. Hirshberg B, Gural A, Caraco Y. Zuclo- thixol (6Ð12). penthixol-associated neutropenia and thrombocytopenia. Ann Pharmacother, 2000;34(6): Thrombocytopenia is usually defined as a 740Ð2. platelet count of less than 150 x 109/L or a 50% decrease in the platelet count from 9. Huynh M, Chee K, Lau DH. Thrombotic baseline (6). Some reports define drug- thrombocytopenic purpura associated with induced thrombocytopenia as a platelet quetiapine. Ann Pharmacother, 2005;39(7Ð 8):1346-8. count of less than 100 x 109/L (6). Al- though relatively rare, drug-induced 10. Watson TD, Stark JE, Vesta KS. thrombocytopenia may be associated Pantoprazole-induced thrombocytopenia. Ann with risks of morbidity and mortality (6). Pharmacother, 2006;40(4):758Ð61. Perhaps because of its low incidence and idiosyncratic nature, drug-induced 11. Celexa (citalopram hydrobromide tablets) thrombocytopenia has often gone unrec- [product monograph]. Montreal: Lundbeck ognized during early clinical trials of drugs Canada Inc.; 2006. and was first reported after marketing (6). 12. Clozaril (clozapine tablets) [product Extracted from Canadian Adverse Reaction monograph]. Dorval (QC): Novartis Pharma- Newsletter, Volume 17, Number 2, 2007 ceuticals Canada Inc.; 2006.

References Aprotinin: hypersensitivity 1. Seroquel (quetiapine fumarate tablets) reactions and renal [product monograph]. Mississauga (ON): AstraZeneca Canada Inc.; 2006. dysfunction Canada — Health Canada has informed 2. Eltookhy A, Pearson NL. Drug-induced pancreatitis. Can Pharmacists J, 2006;139(6): hospitals and pharmacies of an associa- 58Ð60. tion of aprotinin (Trasylol¨) with hypersensitivity reactions and renal dysfunc- 3. Gropper D, Jackson CW. Pancreatitis tion. Aprotinin is indicated for prophylactic associated with quetiapine use. J Clin use to reduce perioperative blood loss Psychopharmacol, 2004;24(3):343Ð5. and the need for blood transfusion in

89 Safety and Efficacy Issues WHO Drug Information Vol 21, No. 2, 2007 those patients undergoing cardiopulmo- Metoclopramide in children: nary bypass in the course of coronary extrapyramidal symptoms artery bypass graft (CABG) surgery who are at increased risk for blood loss and Netherlands — Following an increase in blood transfusion requirement. the number of registered cases of extrapyramidal symptoms in children The authorized indication for Trasylol¨ is receiving metoclopramide, the Medicines restricted to those patients undergoing Evaluation Board has restricted the use of cardiopulmonary bypass in the course of metoclopramide in this population to coronary artery bypass graft (CABG) treatment of severe nausea and vomiting surgery who are at increased risk for of known origin, and only if treatment with blood loss and blood transfusion. other products is ineffective or is not possible. Trasylol¨ administration may cause fatal and nonfatal anaphylactic or anaphylac- The MEB considers there are better toid reactions. Fatal reactions have alternatives to metoclopramide. For occurred with an initial (test) dose as well example, domperidone is a better choice as with any of the components of the in treating post-operative nausea in dose regimen. Fatal reactions have also children. Domperidone is also the drug of occurred in situations where the initial choice in treating migraine in children (test) dose was tolerated. As a result, because the risk of extrapyramidal effects Trasylol¨ should only be administered in is lower than with metoclopramide. operative settings where cardiopulmonary Similarly, 5-HT3 receptor antagonists bypass can be rapidly initiated. (e.g. ondansetron) are the drugs of choice in nausea due to strongly emeto- The risk for anaphylactic or anaphylactoid genic chemotherapy because of better reactions is increased among patients efficacy and fewer adverse events. with prior aprotinin exposure, and a history of any prior aprotinin exposure Reference: News and Publications. The Medicines Evaluation Board, the Netherlands, must be sought prior to Trasylol¨ admin- 21 February 2007. http://www.cbg-meb.nl/uk/ istration. The risk for a fatal reaction nieuws appears to be greater upon re-exposure. As a result, administration of Trasylol¨ to patients with a known or suspected Drug-eluting stents: previous aprotinin exposure during the to be used with caution last 12 months is contraindicated. Sweden — The Swedish Medical Prod- ucts Agency (MPA), in conjunction with Trasylol¨ administration increases the the National Board of Health and Welfare risk of renal dysfunction and may in- and the Swedish Society of Cardiology, crease the need for dialysis in the has recommended utmost restraint in the perioperative period. This risk may be use of drug-eluting stents. The recom- especially increased for patients with pre- mendation was based on the results of existing renal impairment or those who clinical studies, including the Swedish receive aminoglycoside antibiotics or Coronary and Angioplasty Registry drugs that alter renal function. (SCAAR) study that showed increased Reference: Information Update 2007-36, 31 risk of thrombosis associated with the use March 2007: Communication from Bayer Inc. of drug-eluting stents. The results of the on http://.www.hc-sc.gc.ca SCAAR study and four other randomized studies showed that drug-eluting stents

90 WHO Drug Information Vol 21, No. 2, 2007 Safety and Efficacy Issues

have no advantages in terms of myocar- mia is due to the disease itself. Therefore, dial infarction or mortality, compared with none of the ESAs are indicated in this bare-metal stents; in addition, the SCAAR patient population. Recent clinical studies study data indicated a small, long-term have provided new safety information increased risk of these events. According regarding the use of ESAs, including risks to the MPA, drug-eluting stents must only of tumour progression and serious be used in patients for whom no other cardiovascular events. treatment alternative exists or in patients who are at greatly increased risk of ESAs increased the risk of death and of restenosis and for whom the effect of serious cardiovascular adverse events in restenosis is expected to be severe. patients with cancer or renal failure, when treated to a target haemoglobin level of Reference: Swedish Medical Products greater than 120 g/L. Agency, 13 February 2007. http://www.lake- An increased risk of death was seen in medelesverket.se. cancer patients with active malignant disease, who were not being treated with Darbepoetin alfa and epoetin either radiation or chemotherapy and who alfa: update for non-myeloid were treated with ESAs to a target malignancies haemoglobin level of 120 g/L. ESAs are not indicated in this patient population. Canada — The manufacturers of the erythropoiesis-stimulating agents (ESAs), ESAs shortened the time to tumour have updated safety information based progression in patients with advanced on completed or ongoing clinical studies head and neck cancer receiving radiation regarding treatment with darbepoetin alfa therapy; in addition, ESAs decreased (Aranesp¨) and epoetin alfa (Eprex¨). overall survival and increased deaths at 4 months, attributed to disease progres- Darbepoetin alfa is indicated for the sion in patients with metastatic breast treatment of anaemia associated with cancer receiving chemotherapy, when chronic renal failure, and for the treatment these groups of patients were treated to a of anaemia in patients with non-myeloid target haemoglobin level of greater than malignancies, where anaemia is due to 120 g/L. the effect of concomitantly administered chemotherapy. Reference: Communication from Amgen Canada, Inc. 16 April 2007 on http://www.hc- Epoetin alfa (Eprex¨) is indicated for the sc.gc.ca treatment of anaemia associated with chronic renal failure, the treatment of Ayurvedic and Chinese anaemia in patients with non-myeloid medicines: heavy metals malignancies, where anaemia is due to the effect of concomitantly administered Australia — The Therapeutic Goods chemotherapy, the treatment of anaemia Administration (TGA) has released a in zidovudine-treated/HIV-infected pa- statement about the safety of Ayurvedic tients, and for the treatment of patients medicines in Australia, in response to undergoing major elective surgery to recent research into the toxic content of facilitate autologous blood collection, and heavy metals found in some Ayurvedic to reduce allogeneic blood exposure. medicines (1).

Epoetin alfa is no longer indicated in the There are several possible explanations treatment of anaemia in patients with for the presence of heavy metals in non-myeloid malignancies, where anae- traditional herbal remedies (2). Salts of

91 Safety and Efficacy Issues WHO Drug Information Vol 21, No. 2, 2007

heavy metals (for example those of lead, Another FDA review of ADHD medicines mercury and arsenic) are used as princi- revealed a slight increased risk (about 1 pal ingredients in some traditional Indian per 1000) for drug-related psychiatric and (to a lesser extent) Chinese herbal adverse events, such as hearing voices, remedies (4). In addition, cross-contami- becoming suspicious for no reason, or nation of ingredients can occur between becoming manic, even in patients who these types of products and products not did not have previous psychiatric prob- intended to contain metal salts if manu- lems. facturing conditions are not controlled. The medicines that are the focus of the The possibility of contamination and revised labelling and new Patient Medi- adulteration should be considered for any cation Guides include the following: herb or herbal medicine purchased over- seas or imported for personal use, or Adderall¨ (mixed salts of a single entity obtained over the internet. amphetamine product) Tablets

Extracted from Australian Adverse Drug Adderall¨ XR (mixed salts of a single entity Reactions Bulletin, Volume 26, Number 1, amphetamine product) Extended-Release 2007 Capsules

References Concerta¨ (methylphenidate hydrochloride) Extended-Release Tablets 1. Safety of Ayurvedic medicine in Australia. www.tga.gov.au/cm/ayurvedic.htm Daytrana¨ (methylphenidate) Transdermal System 2. Ernst E. Contamination of herbal medicines. The Pharmaceutical Journal 2005; 275; 167 Desoxyn¨ (methamphetamine HCl) Tablets

3. Pharmacopoeia of the People’s Republic of Dexedrine¨ (dextroamphetamine sulfate) China. Beijing, China: People’s Medical Publishing House 2005. Spansule¨ Capsules and Tablets

ADHD drugs: cardiovascular Focalin¨ (dexmethylphenidate hydrochloride) Tablets and psychiatric events Focalin¨ XR (dexmethylphenidate hydro- United States of America — The Food chloride) Extended-Release Capsules and Drug Administration (FDA) has directed the manufacturers of all drug Metadate¨ CD (methylphenidate hydrochlo- products approved for the treatment of ride) Extended-Release Capsules Attention Deficit Hyperactivity Disorder (ADHD) to develop Patient Medication Methylin¨ (methylphenidate hydrochloride) Guides concerning risks of possible Oral Solution cardiovascular and psychiatric events. Methylin¨ (methylphenidate hydrochloride) An FDA review of reports of serious Chewable Tablets cardiovascular adverse events in patients taking usual doses of ADHD products Ritalin¨ (methylphenidate hydrochloride) revealed reports of sudden death in Tablets patients with underlying serious heart Ritalin¨ SR (methylphenidate hydrochlo- problems or defects, and reports of stroke ride) Sustained-Release Tablets and heart attack in adults with certain risk factors.

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Ritalin¨ LA (methylphenidate hydrochloride) tion may be associated with serious Extended-Release Capsules effects such as intestinal obstruction, Strattera¨ (atomoxetine HCl) Capsules bowel perforation and toxic megacolon.

Reference: FDA News, P07-26, 21 February In addition to reports of constipation 2007 with draft Patient Medication Guides for associated with clozapine, there have each product at http://www.fda.gov/cder/drug/ been three reports of paralytic ileus and a infopage/ADHD/default.htm. further three reports of oesophageal dysmotility. These case reports suggest Clozapine can impair motility that clozapine may reduce GI motility of the entire GI tract throughout the gut, resulting in complications higher in the GI tract. New Zealand — Clozapine (Clozaril®, Clopine¨) is an atypical antipsychotic that Many anticholinergic drugs can cause GI is effective for treatment-resistant schizo- dysmotility, but clozapine has a much phrenia. It causes agranulocytosis in up more potent effect through its interaction to 1% of patients (1) and regular monitor- with multiple receptors (including anti- ing of neutrophil counts is mandatory cholinergic and serotonergic receptors) throughout treatment. In New Zealand affecting GI activity. This action is exacer- one death from agranulocytosis has been bated by co-prescription of anticholinergic reported. In contrast, four deaths from agents such as benztropine and tricyclic complications of severe constipation have antidepressants. been reported to the Intensive Medicines References Monitoring Programme. Health professionals are reminded that the gastro- 1. Alvir JMJ, Lieberman JA, Safferman AZ, et intestinal (GI) effects of clozapine are al. Clozapine-induced agranulocytosis. New potentially serious. England Journal of Medicine 1993;329:162- 167 Constipation is often regarded as a frequent, minor side effect of clozapine. 2. PM Ellis. Clozapine: Fatal ‘constipation’ However, review of New Zealand reports more common than fatal agranulocytosis. shows that clozapine-induced constipa- Prescriber Update. March 2007. http:// www.medsafe.govt.nz

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adverse drug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information". All signals must be validated before any regulatory decision can be made.

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Essential Medicines

15th Model List affected by certain conditions such as respiratory tract infections, malaria and of Essential Medicines diarrhoeal diseases — particularly in developing countries. An estimated 10.6 Model List updated million children under five die every year, The WHO Model List of Essential Medi- many from treatable conditions. In 2005, cines allows countries to select medicines 2.3 million children under 15 years were of public health priority, address problems HIV positive. of cost and availability and provides guidance to pharmaceutical manufacturers on In spite of the huge need, there are few medicine needs. formulations appropriate for children or that can be easily consumed by a child. During its 2007 meeting in Geneva, the At present, children must often take WHO Expert Committee on Essential crushed adult tablets, with little evidence Medicines made a number of important to guide the efficacy and safety of the updates to the Model List of Essential dose. When medicines do exist in the Medicines (set out on the following right dosage they are usually in syrup pages). These included the addition of form, which may pose supply, storage five fixed-dose-combinations to treat HIV/ and pricing problems in developing AIDS in adults, two of which are available countries. in generic form, and antimalarials recommended by WHO. The challenge for children becomes more acute when they are affected by a condi- Five oral liquid formulations were in- tion requiring combination therapy, such cluded for children — three for epilepsy, as HIV/AIDS and malaria. In these cases, one for children born prematurely, and fixed dose combination tablets are re- one new medicine for HIV/AIDS. Three quired. While production of adult fixed- other epilepsy medicines were included in dose-combinations is increasing, these the form of chewable, dispersable tablets are lacking for children. In addition, anti- which are also effective in children. retrovirals for children are currently three times more expensive than the adult A medicines list for children versions. Following recommendations from the Expert Committee, work will begin to WHO will also work with partners to create a list if essential medicines specifi- advocate innovation and research into cally tailored to children’s needs. A group children’s medicines, manufacture of new of experts will meet in July 2007 to begin dosage forms and new formulas, and work on a list of medicines to address mechanisms to relay information about diseases of high mortality and morbidity children’s medicines to countries quickly in children. and effectively.

Children suffer from the same illnesses Reference: WHO News Release. WHO/17. 13 as adults but they are more seriously April 2007 http://www.who.int

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WHO Model List of Essential Medicines 15th Edition, revised March 2007

Explanatory Notes The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost-effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment.

The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed. In case of doubt medicines may also be listed as complementary on the basis of consistent higher costs or less attractive cost-effectiveness in a variety of settings.

The square box symbol (■ ) is primarily intended to indicate similar clinical performance within a pharmacological class. The listed medicine should be the example of the class for which there is the best evidence for effectiveness and safety. In some cases, this may be the first medicine that is licensed for marketing; in other instances, subsequently licensed compounds may be safer or more effective. Where there is no difference in terms of efficacy and safety data, the listed medicine should be the one that is generally available at the lowest price, based on international drug price information sources. Therapeutic equivalence is only indicated on the basis of reviews of efficacy and safety and when consistent with WHO clinical guidelines. National lists should not use a similar symbol and should be specific in their final selection, which would depend on local availability and price. Medicines are listed in alphabetical order, within sections.

The presence of an entry on the Essential Medicines List carries no assurance as to pharmaceutical quality. It is the responsibility of each local regulatory authority to ensure that each brand is of appropriate pharmaceutical quality (including stability) and that, when relevant, different brands are interchangeable.

Dosage forms of medicines are listed in alphabetical order and there is no implication of pref- erence for one form over another. Standard treatment guidelines should be consulted for information on appropriate dosage forms.

Entries of the type oral liquid are intended to permit any solution, suspension or other form of liquid. Granules for reconstitution as an oral liquid may substitute for oral liquids, and typically carry benefits in the form of better stability and lower transport costs. If more than one type of oral liquid is available on the same market (e.g. solution, suspension, granules for reconstitution), they may be interchanged and in such cases should be bioequivalent. It is preferable that oral liquids do not contain sugar, and that solutions for children do not contain alcohol.

Entries of the type tablet are intended to allow various forms of immediate-release tablet such as uncoated, film-coated, crushable, chewable, dispersible etc. Enteric coating, on the other hand, modifies drug release, and enteric-coated products are a modified release dosage form. Crushable, chewable and dispersible tablets may be easier to administer to paediatric populations and to the elderly.

95 15th Model List of Essential Medicines WHO Drug Information Vol 21, No. 2, 2007

1. Anaesthetics 2. Analgesics, antipyretics, nonsteroidal anti-inflammatory 1.1 General anaesthetics and oxygen medicines (NSAIMs), medi- ■ halothane inhalation cines used to treat gout and ketamine injection: 50 mg disease modifying agents in (as hydrochloride)/ rheumatoid disorders ml in 10-ml vial (DMARDs) nitrous oxide inhalation 2.1 Nonopioids and nonsteroidal anti- oxygen inhalation (medicinal gas) inflammatory medicines (NSAIMs) ■ thiopental powder for injection: 0.5 g, 1.0 g (sodium salt) in ampoule acetylsalicylic acid Suppository: 50Ð150 mg Tablet: 100Ð500 mg 1.2 Local anaesthetics ibuprofen Tablet: 200 mg; 400 mg ■ bupivacaine Injection: 0.25%; 0.5% (hydrochloride) in via. paracetamol* Oral liquid: 125 mg/5 m

Injection for spinal anaesthesia: Suppository: 100 mg 0.5% (hydrochloride) in 4-ml ampoule to be mixed with 7.5% glucose solution Tablet: 100Ð500 mg

■ lidocaine Injection: 1%; 2% * Not recommended for anti-inflammatory use due (hydrochloride) in vial to lack of proven benefit to that effect.

Injection for spinal anaesthesia: 2.2 Opioid analgesics 5% (hydrochloride) in 2-ml ampoule to be mixed with 7.5% glucose solution codeine Tablet: 30 mg (phosphate)

Topical forms: 2Ð4% (hydrochloride) morphine Injection: 10 mg (morphine hydrochloride or morphine lidocaine + epinephrine Dental cartridge: sulfate) in 1-ml ampoule (adrenaline) 2% (hydrochloride) + epinephrine 1:80 000 Oral liquid: 10 mg (morphine hydrochloride or morphine Injection: 1%; 2% (hydrochloride) + sulfate)/5 ml epinephrine 1:200 000 in vial Tablet: 10 mg (morphine sulfate) Complementary List Tablet (prolonged release): 10 mg; ephedrine Injection: 30 mg (hydro- 30 mg; 60 mg (morphine sulfate) chloride)/ml in 1-ml ampoule (For use in spinal anaesthesia 2.3 Medicines used to treat gout during delivery, to prevent hypotension) allopurinol Tablet: 100 mg 1.3 Preoperative medication and sedation 2.4 Disease modifying agents used in for short-term procedures rheumatoid disorders (DMARDs) atropine Injection: 1 mg (sulfate) chloroquine Tablet: 100 mg; 150 mg in 1-ml ampoule (as phosphate or sulfate).

■ diazepam Injection: 5 mg/ml in 2-ml ampoule Complementary List Tablet: 5 mg azathioprine Tablet: 50 mg morphine Injection: 10 mg (sulfate or methotrexate Tablet: 2.5 mg (as sodium salt) hydrochloride) in 1-ml ampoule penicillamine Capsule or tablet: 250 mg promethazine Oral liquid: 5 mg (hydrochloride)/5 ml sulfasalazine Tablet: 500 mg

96 WHO Drug Information Vol 21, No. 2, 2007 15th Model List of Essential Medicines

3. Antiallergics and medi- sodium nitrite Injection: 30 mg/ml cines used in anaphylaxis in 10-ml ampoule sodium thiosulfate Injection: 250 mg/ml ■ chlorphenamine Injection: 10 mg (hydrogen in 50-ml ampoule maleate) in 1-ml ampoule

Tablet: 4 mg (hydrogen maleate) 5. Anticonvulsants/anti- epileptics dexamethasone Injection: 4 mg dexamethasone phosphate (as disodium salt) carbamazepine Oral liquid: 100 mg/5 ml in 1-ml ampoule Tablet (chewable): epinephrine (adrenaline) Injection: 1 mg (as 100 mg; 200 mg hydrochloride or hydrogen tartrate) in 1-ml ampoule Tablet (scored): 100 mg; 200 mg hydrocortisone Powder for injection: 100 mg ■ diazepam Injection: 5 mg/ml in 2-ml (as sodium succinate) in vial ampoule (intravenous or rectal) ■ prednisolone* Tablet: 5 mg; 25 mg magnesium sulfate* Injection: 500 mg/ml in 2-ml ampoule; 500 mg/ml in * There is no evidence for complete clinical simil- 10-ml ampoule arity between prednisolone and dexamethasone at high doses. * For use in eclampsia and severe pre-eclampsia and not for other convulsant disorders.

4. Antidotes and other sub- phenobarbital Injection: 200 mg/ml stancess used in poisonings (phenobarbital sodium)

4.1 Non-specific Oral liquid: 15 mg/5 ml (phenobarbital) or 5 ml (phenobarbital sodium) charcoal, activated Powder Tablet: 15-100 mg (phenobarbital) 4.2 Specific phenytoin Capsule: 25 mg; 50 mg; acetylcysteine Injection: 200 mg/ml in 100 mg (sodium salt) 10-ml ampoule Injection: 50 mg/ml in 5-ml vial (sodium salt) atropine Injection: 1 mg (sulfate) in 1-ml ampoule Oral liquid: 25-30 mg/5 ml.* calcium gluconate Injection: 100 mg/ml in Tablet: 25 mg; 50 mg; 10-ml ampoule 100 mg (sodium salt) deferoxamine Powder for injection: 500 mg Tablet (chewable): 50 mg (mesilate) in vial * The presence of both 25 mg/5 ml and 30 mg/5 ml dimercaprol Injection in oil: 50 mg/ml strengths on the same market would cause confu- in 2-ml ampoule sion in prescribing and dispensing and should be avoided. DL-methionine Tablet: 250 mg valproic acid Oral liquid: 200 mg/5 ml methylthioninium chloride Injection: 10 mg/ml in (methylene blue) 10-ml ampoule Tablet (crushable): 100 mg naloxone Injection: 400 micrograms Tablet (enteric-coated): 200 mg; (hydrochloride) in 1-ml ampoule 500 mg (sodium valproate) penicillamine Capsule or tablet: 250 mg Complementary List potassium ferric hexacyano- Powder for oral ethosuximide Capsule: 250 mg ferrate(II) -2H 0 (Prussian blue) administration 2 Oral liquid: 250 mg/5 ml sodium calcium edetate Injection: 200 mg/ml in 5-ml ampoule

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6. Anti-infective medicines ampicillin Powder for injection: 500 mg; 1 g (as sodium salt) in vial

6.1 Anthelminthics benzathine benzylpenicillin Powder for injection: 6.1.1 Intestinal anthelminthics 1.44 g benzylpenicillin (=2.4 million IU) in 5-ml vial albendazole Tablet (chewable): 400 mg benzylpenicillin Powder for injection: 600 mg levamisole Tablet: 50 mg; 150 mg (= 1 million IU); 3 g (= 5 million IU) (as hydrochloride) (sodium or potassium salt) in vial ■ mebendazole Tablet (chewable): 100 mg; cefazolin* Powder for injection: 1 g 500 mg (as sodium salt) in vial niclosamide* Tablet (chewable): 500 mg * For surgical prophylaxis.

* Niclosamide is listed for use when praziquantel cefixime* Capsule: 400 mg treatment fails. * Only listed for single-dose treatment of uncompli- praziquantel Tablet: 150 mg; 600 mg cated ano-genital gonorrhoea. pyrantel Oral liquid: 50 mg (as embonate)/ml ■ cloxacillin Powder for injection: 500 mg (as sodium salt) in vial Tablet (chewable): 250 mg (as embonate) Capsule: 500 mg; 1 g (as sodium salt) 6.1.2 Antifilarials Powder for oral liquid: 125 mg (as sodium salt)/5 ml ivermectin Tablet (scored): 3 mg; 6 mg phenoxymethylpenicillin Powder for oral liquid: Complementary List 250 mg (as potassium salt)/5 ml diethylcarbamazine Tablet: 50 mg; 100 mg Tablet: 250 mg (as potassium salt) (dihydrogen citrate) procaine benzylpenicillin Powder for injection: suramin sodium Powder for injection: 1 g in vial 1 g (=1 million IU); 3 g (=3 million IU) in vial 6.1.3 Antischistosomals and antitrematode medicine Complementary List praziquantel Tablet: 600 mg ceftazidime Powder for injection: 250 mg (as pentahydrate) in vial triclabendazole Tablet: 250 mg ■ ceftriaxone Powder for injection: 250 mg, Complementary List 1 g (as sodium salt) in vial oxamniquine* Capsule: 250 mg imipenem* + Powder for injection: cilastatin * 250 mg (as monohydrate) + Oral liquid: 250 mg/5 ml 250 mg (as sodium salt); 500 mg (as monohydrate) + * Oxamniquine is listed for use when praziquantel 500 mg (as sodium salt) in vial treatment fails. * Only listed for the treatment of life-threatening hos- 6.2 Antibacterials pital-based infection due to suspected or proven multidrug-resistant infection. 6.2.1 Beta Lactam medicines amoxicillin Capsule or tablet: 250 mg; 6.2.2 Other antibacterials 500 mg (anhydrous) azithromycin* Capsule: 250 mg or 500 mg Powder for oral liquid: 125 mg Oral liquid: 200 mg/5 ml (anhydrous)/5 ml * Only listed for single-dose treatment of genital amoxicillin + Tablet: 500 mg + 125 mg Chlamydia trachomatis and of trachoma. clavulanic acid

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chloramphenicol Capsule: 250 mg sulfadiazine Injection: 250 mg (sodium salt) in 4-ml ampoule Oily suspension for injection: 0.5 g (as sodium succinate)/ml Tablet: 500 mg in 2-ml ampoule vancomycin Powder for injection: 250 mg Oral liquid: 150 mg (as palmitate)/5 ml (as hydrochloride) in vial

Powder for injection: 1 g 6.2.3 Antileprosy medicines (sodium succinate) in vial Medicines used in the treatment of leprosy should ■ never be used except in combination. Combination ciprofloxacin* Tablet: 250 mg therapy is essential to prevent the emergence of drug (as hydrochloride) resistance. Colour coded blister packs (MDT blister * Final selection depends on indication for use. packs) containing standard two medicine (paucibacillary leprosy) or three medicine doxycycline* Capsule or tablet: (multibacillary leprosy) combinations for adult and 100 mg (hydrochloride) childhood leprosy should be used. MDT blister packs can be supplied free of charge through WHO. * Final selection depends on indication for use. clofazimine Capsule: 50 mg; 100 mg ■ erythromycin Capsule or tablet: 250 mg (as stearate or ethyl succinate) dapsone Tablet: 25 mg; 50 mg; 100 mg

Powder for injection: 500 mg rifampicin Capsule or tablet: 150 mg; 300 mg (as lactobionate) in vial 6.2.4 Antituberculosis medicines Powder for oral liquid: 125 mg (as stearate or ethyl succinate) ethambutol Tablet: 100Ð400 mg (hydrochloride) ■ gentamicin* Injection: 10 mg; isoniazid Tablet: 100Ð300 mg 40 mg (as sulfate)/ml in 2-ml vial Tablet (scored): 50 mg * Final selection depends on indication for use. isoniazid + ethambutol Tablet: 150 mg + 400 mg ■ metronidazole Injection: 500 mg in 100-ml vial pyrazinamide Tablet: 400 mg

Oral liquid: 200 mg (as benzoate)/5 ml Tablet (dispersible): 150 mg Suppository: 500 mg; 1 g Tablet (scored): 150 mg Tablet: 200-500 mg rifampicin Capsule or tablet: 150 mg; 300 mg nitrofurantoin Tablet: 100 mg rifampicin + isoniazid Tablet: 60 mg + 30 mg; spectinomycin Powder for injection: 2 g 150 mg + 75 mg; 300 mg + 150 mg (as hydrochloride) in vial 60 mg + 60 mg (For intermittent sulfamethoxazole + Injection: 80 mg + 16 mg/ml use three times weekly) trimethoprim in 5-ml and 10-ml ampoules 150 mg + 150 mg (For intermittent Oral liquid: 200 mg + 40 mg/5 ml use three times weekly) Tablet: 100 mg + 20 mg; rifampicin + isoniazid + Tablet: 150 mg + 400 mg + 80 mg ethambutol 75 mg + 275 mg

rifampicin + isoniazid + Tablet: 60 mg + trimethoprim Tablet: 100 mg; 200 mg pyrazinamide 30 mg + 150 mg; Complementary List 150 mg + 75 mg + 400 mg clindamycin Capsule: 150 mg 150 mg + 150 mg + 500 mg (For intermittent use three times weekly) Injection: 150 mg (as phosphate)/ml rifampicin + isoniazid + Tablet: 150 mg + 75 mg + pyrazinamide + ethambutol 400 mg + 275 mg

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streptomycin Powder for injection: 6.4.2 Antiretrovirals 1 g (as sulfate) in vial Based on current evidence and experience of use, Complementary List medicines in the following three classes of antiretro- Reserve second-line drugs for the treatment of virals are included as essential medicines for treat- multidrug-resistant tuberculosis (MDR-TB) should be ment and prevention of HIV (prevention of mother- used in specialized centres adhering to WHO stand- to-child transmission and post exposure prophylaxis). ards for TB control. The Committee emphasizes the importance of using these products in accordance with global and national amikacin Powder for injection: 1000 mg in vial guidelines. The Committee recommends and en- dorses the use of fixed-dose combinations and the ρ-aminosalicylic acid Granules: 4 g in sachet development of appropriate new fixed-dose combi- Tablet: 500 mg nations, including modified dosage forms, non-refrig- erated products and paediatric dosage forms with capreomycin Powder for injection: 1000 mg in vial assured pharmaceutical quality. cycloserine Capsule or tablet: 250 mg 6.4.2.1 Nucleoside/nucleotide reverse transcriptase inhibitors ethionamide Tablet: 125 mg; 250 mg abacavir (ABC) Oral liquid: 100 mg kanamycin Powder for injection: 1000 mg in vial (as sulfate)/5 m ofloxacin* Tablet: 200 mg; 400 mg Tablet: 300 mg (as sulfate)

* Levofloxacin may be an alternative based on didanosine (ddI) Buffered powder for oral liquid: availability and programme considerations. 100 mg; 167 mg; 250 mg packets 6.3 Antifungal medicines Capsule (unbuffered enteric-coated): 125 mg; 200 mg; 250 mg; 400 mg clotrimazole Vaginal cream: 1%; 10% Tablet (buffered chewable, Vaginal tablet: 100 mg; 500 mg dispersible): 25 mg; 50 mg; 100 mg; 150 mg; 200 mg ■ fluconazole Capsule: 50 mg emtricitabine (FTC)* Capsule: 200 mg Injection: 2 mg/ml in vial Oral liquid: 10 mg/ml Oral liquid: 50 mg/5 ml * 3TC is an acceptable alternative to FTC, based on griseofulvin Capsule or tablet: 125 mg; 250 mg knowledge of the pharmacology, the resistance pat- terns and clinical trials of antiretrovirals. nystatin Lozenge: 100 000 IU lamivudine (3TC) Tablet: 150 mg Pessary: 100 000 IU Oral liquid: 50 mg/5 ml Tablet: 100 000 IU; 500 000 IU stavudine (d4T) Capsule: 15 mg; Complementary List 20 mg; 30 mg; 40 mg* amphotericin B Powder for injection: * The Committee expects this dosage form to be 50 mg in vial reviewed for possible deletion at the next meeting. flucytosine Capsule: 250 mg Powder for oral liquid: 5 mg/5 ml

Infusion: 2.5 g in 250 ml tenofovir Capsule: 300 mg (tenofovir disoproxil fumarate Ð equivalent to potassium iodide Saturated solution 245 mg tenofovir disoproxil) 6.4 Antiviral medicines zidovudine Capsule: 100 mg; 250 mg

6.4.1 Antiherpes medicines (ZDV or AZT) Oral liquid: 50 mg/5 ml ■ aciclovir Powder for injection: Solution for IV infusion 250 mg (as sodium salt) in vial injection: 10 mg/ml in 20-ml vial

Tablet: 200 mg Tablet: 300 mg

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6.4.2.2 Non-nucleoside reverse transcriptase zidovudine + lamivudine + Tablet: 300 mg + inhibitors nevirapine 150 mg + 200 mg efavirenz (EFV or EFZ) Capsule: 50 mg; 6.4.3 Other antivirals 100 mg; 200 mg ribavirin Injection for intravenous administration: Oral liquid: 150 mg/5 ml 1000 mg and 800 mg in 10-ml phosphate buffer solution Tablet: 600 mg Oral solid dosage forms: 200 mg; nevirapine (NVP) Oral liquid: 50 mg/5 ml 400 mg; 600 mg Tablet: 200 mg 6.5 Antiprotozoal medicines 6.4.2.3 Protease inhibitors 6.5.1 Antiamoebic and antigiardiasis medicines Selection of protease inhibitor(s) from the Model List will need to be determined by each country after con- diloxanide Tablet: 500 mg (furoate) sideration of international and national treatment guidelines and experience. Ritonavir is recommended ■ metronidazole Injection: 500 mg in 100-ml vial for use in combination as a pharmacological booster, and not as an antiretroviral in its own right. Oral liquid: 200 mg (as benzoate)/5 ml Tablet: 200-500 mg This section will be reviewed by the Committee as a priority at its next meeting. It is expected that appli- 6.5.2 Antileishmaniasis medicines cation for a heat stable tablet formulation containing 200/50 mg lopinavir + ritonavir will be submitted for ■ meglumine antimoniate Injection, 30%, the next meeting. equivalent to approximately 8.1% antimony in 5-ml ampoule indinavir (IDV) Capsule: 200 mg; 333 mg; 400 mg (as sulfate). paromomycin Solution for intramuscular injection: lopinavir + Capsule: 133.3 mg + 33.3 mg 750 mg/2 ml (as sulfate) ritonavir (LPV/r) Complementary List Oral liquid: 400 mg + 100 mg/5 ml amphotericin B Powder for injection: nelfinavir (NFV) Oral powder: 50 mg/g 50 mg in vial

Tablet: 250 mg (as mesilate) pentamidine Powder for injection: 200 mg; 300 mg (isetionate) in vial ritonavir Oral liquid: 400 mg/5 ml 6.5.3 Antimalarial medicines Oral solid dosage form: 100 mg 6.5.3.1 For curative treatment saquinavir (SQV) Capsule: 200 mg Medicines for the treatment of P. falciparum malaria FIXED-DOSE COMBINATIONS cases should be used in combination. The list cur- efavirenz + emtricitabine* Tablet: 600 mg + rently recommends combinations according to treat- + tenofovir 200 mg + 300 mg ment guidelines. The Committee recognizes that not all of these FDCs exist and encourages their devel- * 3TC is an acceptable alternative to FTC, based on opment and rigorous testing. The Committee also knowledge of the pharmacology, the resistance pat- encourages development and testing of rectal dos- terns and clinical trials of antiretrovirals. age formulations. emtricitabine* + tenofovir Tablet: 200 mg + 300 mg amodiaquine* Tablet: 153 mg or 200 mg (as hydrochloride) * 3TC is an acceptable alternative to FTC, based on * To be used (a) in combination with artesunate 50 knowledge of the pharmacology, the resistance pat- mg OR (b) may be used alone for the treatment of terns and clinical trials of antiretrovirals. Plasmodium vivax, P.ovale and P.malariae stavudine + lamivudine + Tablet: 30 mg + infections. nevirapine 150 mg + 200 mg artemether Oily injection: 80 mg/ml zidovudine + lamivudine Tablet: 300 mg + 150 mg in 1-ml ampoule For use in the management of severe malaria.

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artemether + Tablet: 20 mg + 120 mg mefloquine Tablet: 250 mg lumefantrine* (as hydrochloride)

* Not recommended in the first trimester of pregnancy proguanil* Tablet: 100 mg (hydrochloride) or in children below 5 kg. * For use only in combination with chloroquine. artesunate* Injection: ampoules, containing 60 mg anhydrous 6.5.4 Antipneumocystosis and artesunic acid with a separate antitoxoplasmosis medicines ampoule of 5% sodium bicarbonate solution pyrimethamine Tablet: 25 mg For use in the management of severe malaria. sulfamethoxazole + Injection: 80 mg + 16 mg/ml Tablet: 50 mg trimethoprim in 5-ml ampoule; 80 mg + 16 mg/ml in 10-ml ampoule * To be used in combination with either amodiaquine, mefloquine or sulfadoxine + pyrimethamine. Complementary List chloroquine Oral liquid: 50 mg (as pentamidine Tablet: 200 mg; 300 mg phosphate or sulfate)/5 ml 6.5.5 Antitrypanosomal medicines Tablet: 100 mg; 150 mg (as phosphate or sulfate) 6.5.5.1 African trypanosomiasis doxycycline* Capsule: 100 mg (as hydrochloride) Medicines for the treatment of 1st stage African trypanosomiasis Tablet (dispersible): 100 mg (as monohydrate) pentamidine* Powder for injection: 200 mg (pentamidine isetionate) in vial * For use only in combination with quinine. * To be used for the treatment of Trypansoma brucei mefloquine* Tablet: 250 mg (as hydrochloride) gambiense infection. * To be used in combination with artesunate 50 mg suramin sodium* Powder for injection: 1 g in vial. primaquine* Tablet: 7.5 mg; * To be used exclusively for the treatment of the ini- 15 mg (as diphosphate) tial phase of T. brucei rhodesiense infection. * Only for use to achieve radical cure of P.vivax and Medicines for the treatment of P.ovale infections, given for 14 days. 2nd stage African trypanosomiasis quinine* Injection: 300 mg quinine eflornithine Injection: 200 mg hydrochloride/ml in 2-ml ampoule (hydrochloride)/ml in 100-ml bottle Tablet: 300 mg (quinine sulfate) melarsoprol Injection: 3.6% solution, or 300 mg (quinine bisulfate) 5-ml ampoules (180 mg * For use only in the management of severe malaria, of active compound) and should be used in combination with doxycycline. 6.5.5.2 American trypanosomiasis sulfadoxine + * Tablet: 500 mg + 25 mg benznidazole Tablet: 100 mg pyrimethamine nifurtimox Tablet: 30 mg; 120 mg; 250 mg * Only in combination with artesunate 50 mg 6.5.3.2 For prophylaxis 7. Antimigraine medicines chloroquine* Oral liquid: 50 mg (as 7.1 For treatment of acute attack phosphate or sulfate)/5 ml acetylsalicylic acid Tablet: 300-500 mg Tablet: 150 mg (as phosphate or sulfate) paracetamol Tablet: 300-500 mg * For use only in central American regions for P.vivax. 7.2 For prophylaxis doxycycline Capsule or tablet: ■ propranolol Tablet: 20 mg; 40 mg 100 mg ( hydrochloride) (hydrochloride)

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8. Antineoplastic, immuno- mercaptopurine Tablet: 50 mg suppressives and medicines methotrexate Powder for injection: used in palliative care 50 mg (as sodium salt) in vial Tablet: 2.5 mg (as sodium salt) 8.1 Immunosuppressive medicines procarbazine Capsule: 50 mg (as hydrochloride)

Complementary List vinblastine Powder for injection: 10 mg (sulfate) in vial azathioprine Powder for injection: 100 mg (as sodium salt) in vial vincristine Powder for injection: 1 mg; 5 mg (sulfate) in vial Tablet: 50 mg ciclosporin Capsule: 25 mg 8.3 Hormones and antihormones

Concentrate for injection: 50 mg/ml in Complementary List 1-ml ampoule for organ transplantation dexamethasone Injection: 4 mg 8.2 Cytotoxic medicines dexamethasone phosphate (as disodium salt) in 1-ml ampoule This section is expected to be reviewed at the next meeting. hydrocortisone Powder for injection: 100 mg (as sodium succinate) in vial Complementary List ■ prednisolone* Tablet: 5 mg; 25 mg asparaginase Powder for injection: * There is no evidence for complete clinical similarity 10 000 IU in vial between prednisolone and dexamethasone at high bleomycin Powder for injection: doses. 15 mg (as sulfate) in vial tamoxifen Tablet: 10 mg; 20 mg (as citrate) calcium folinate Injection: 3 mg/ml in 10-ml ampoule 8.4 Medicines used in palliative care

Tablet: 15 mg The WHO Expert Committee recognizes the importance of listing specific medicines in the Palliative chlorambucil Tablet: 2 mg Care Section. Some medicines currently used in palliative care are included in the relevant sections of cisplatin Powder for injection: the Model List, according to their therapeutic use, e.g. 10 mg; 50 mg in vial analgesics. The Guidelines for Palliative Care that were referenced in the previous list are in need of cyclophosphamide Powder for injection: update. The Committee expects applications for medi- 500 mg in vial cines needed for palliative care to be submitted for Tablet: 25 mg the next meeting. cytarabine Powder for injection: 100 mg in vial 9. Antiparkinsonism medicines dacarbazine Powder for injection: 100 mg in vial biperiden Injection: 5 mg (lactate) dactinomycin Powder for injection: in 1-ml ampoule 500 micrograms in vial Tablet: 2 mg (hydrochloride) daunorubicin Powder for injection: levodopa + ■ carbidopa Tablet: 100 mg + 10 mg; 50 mg (as hydrochloride) 250 mg + 25 mg doxorubicin Powder for injection: 10 mg; 50 mg (hydrochloride) in vial 10. Medicinces affecting the blood etoposide Capsule: 100 mg

Injection: 20 mg/ml in 5-ml ampoule 10.1 Antianaemia medicines fluorouracil Injection: 50 mg/ml ferrous salt Oral liquid: equivalent to 25 mg in 5-ml ampoule iron (as sulfate)/ml

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Tablet: equivalent to 60 mg iron glyceryl trinitrate Tablet (sublingual): 500 micrograms ferrous salt + Tablet equivalent to 60 mg iron + folic acid 400 micrograms folic acid ■ isosorbide dinitrate Tablet (sublingual): 5 mg (Nutritional supplement for use during pregnancy) verapamil Tablet: 40 mg; folic acid Tablet: 1 mg; 5 mg 80 mg (hydrochloride) hydroxocobalamin Injection: 1 mg in 12.2 Antiarrhythmic medicines 1-ml ampoule This subsection will be reviewed at the next meeting 10.2 Medicines affecting coagulation of the Expert Committee. heparin sodium Injection: 1000 IU/ml; ■ atenolol Tablet: 50 mg; 100 mg 5000 IU/ml; 20,000 IU/ml in 1-ml ampoule digoxin Injection: 250 micrograms/ ml in 2-ml ampoule phytomenadione Injection: 10 mg/ml in 5-ml ampoule Oral liquid: 50 micrograms/ml

Tablet: 10 mg Tablet: 62.5 micrograms; 250 micrograms protamine sulfate Injection: 10 mg/ml in 5-ml ampoule epinephrine Injection: 100 micrograms/ml (adrenaline) (as acid tartrate or hydrochloride) ■ warfarin Tablet: 1 mg; 2 mg; 5 mg (sodium salt) in 10-ml ampoule

lidocaine Injection: 20 mg (hydrochloride)/ 11. Blood products and ml in 5-ml ampoule plasma substitutes verapamil Injection: 2.5 mg (hydrochloride)/ 11.1 Plasma substitutes ml in 2-ml ampoule

■ dextran 70* Injectable solution: 6% Tablet: 40 mg; 80 mg (hydrochloride)

* Polygeline, injectable solution, 3.5% is considered Complementary List as equivalent ■ procainamide Injection: 100 mg (hydro- 11.2 Plasma fractions for specific use chloride)/ml in 10-ml ampoule. ■ quinidine Tablet: 200 mg (sulfate) All plasma fractions should comply with the WHO Requirements for the Collection, Processing and 12.3 Antihypertensive medicines Quality Control of Blood, Blood Components and Plasma Derivatives (Revised 1992). (WHO Techni- ■ amlodipine Tablet: 5 mg cal Report Series, No. 840, 1994, Annex 2). ■ atenolol Tablet: 50 mg; 100 mg Complementary List ■ enalapril Tablet: 2.5 mg human normal Intravenous administration: immunoglobulin 5%, 10% protein solution hydralazine* Powder for injection: 20 mg (hydrochloride) in ampoule Intramuscular administration: 16% protein solution Tablet: 25 mg, 50 mg (hydrochloride)

■ factor VIII concentrate Dried * Hydralazine is listed for use in the acute management of severe pregnancy-induced hypertension only. ■ factor IX complex Dried Its use in the treatment of essential hypertension is (coagulation factors, II, VII, not recommended in view of the availability of more IX, X) concentrate evidence of efficacy and safety of other medicines. 12. Cardiovascular medicines ■ hydrochlorothiazide Tablet (scored): 25 mg methyldopa* Tablet: 250 mg 12.1 Antianginal medicines * Methyldopa is listed for use in the management of ■ atenolol Tablet: 50 mg; 100 mg pregnancy-induced hypertension only. Its use in the

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treatment of essential hypertension is not recom- Complementary List mended in view of the availability of more evidence of efficacy and safety of other medicines. selenium sulfide Detergent-based suspension: 2% Complementary List 13.2 Anti-infective medicines sodium nitroprusside Powder for infusion: ■ methylrosanilinium Aqueous solution: 0.5% 50 mg in ampoule chloride (gentian violet) 12.4 Medicines used in heart failure Tincture: 0.5% neomycin sulfate + Ointment: 5 mg neomycin This subsection will be reviewed at the next meeting ■ bacitracin sulfate + 250 IU of the Expert Committee. bacitracin zinc/g digoxin Injection: 250 micrograms/ potassium permanganate Aqueous solution: ml in 2-ml ampoule 1:10 000

Oral liquid: 50 micrograms/ml silver sulfadiazine Cream: 1%, in 500-g container Tablet: 62.5 micrograms; 250 micrograms 13.3 Anti-inflammatory and antipruritic ■ enalapril Tablet: 2.5 mg medicines

■ furosemide Injection: 10 mg/ml ■ betamethasone Ointment or cream: in 2-ml ampoule 0.1% (as valerate)

Tablet: 40 mg ■ calamine lotion Lotion ■ hydrocortisone Ointment or cream: ■ hydrochlorothiazide Tablet (scored): 25 mg 1% (acetate) Complementary List 13.4 Astringent medicines dopamine Injection: 40 mg (hydrochloride) in 5-ml vial aluminium diacetate Solution: 5% 12.5 Antithrombotic medicines 13.5 Medicines affecting skin differentiation and proliferation acetylsalicylic acid Tablet: 100 mg benzoyl peroxide Lotion or cream: 5% Complementary List coal tar Solution: 5% streptokinase Powder for injection: 1.5 million IU in vial dithranol Ointment: 0.1%-2% 12.6 Lipid-lowering agents fluorouracil Ointment: 5%

■ simvastatin* Tablet: 5 mg; 10 mg; ■ podophyllum resin Solution: 10-25% 20 mg; 40 mg salicylic acid Solution: 5% * For use in high-risk patients. urea Ointment or cream: 10% 13. Dermatological medicines 13.6 Scabicides and pediculicides (topical) ■ benzyl benzoate Lotion: 25%

13.1 Antifungal medicines permethrin Cream: 5% benzoic acid + Ointment or cream: 6% + 3% Lotion: 1% salicylic acid 14. Diagnostic agents ■ miconazole Ointment or cream: 2% (nitrate) sodium thiosulfate Solution: 15% 14.1 Ophthalmic medicines fluorescein Eye drops: 1% (sodium salt)

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■ tropicamide Eye drops: 0.5% Oral liquid: 75 mg/5 ml 14.2 Radiocontrast media Tablet: 150 mg (as hydrochloride) magnesium Oral liquid: equivalent to ■ amidotrizoate Injection: 140-420 mg iodine hydroxide 550 mg magnesium oxide/10 ml (as sodium or meglumine salt)/ ml in 20-ml ampoule 17.2 Antiemetic medicines barium sulfate Aqueous suspension metoclopramide Injection: 5 mg (hydrochloride)/ ml in 2-ml ampoule ■ iohexol Injection: 140-350 mg iodine/ ml in 5-ml; 10-ml; 20-ml ampoule Tablet: 10 mg (hydrochloride)

Complementary List promethazine Injection: 25 mg (hydrochloride)/ ml in 2-ml ampoule ■ meglumine iotroxate Solution: 5-8 g iodine in 100-250 ml Oral liquid: 5 mg (hydrochloride)/5 ml 15. Disinfectants and antiseptics Tablet: 10 mg; 25 mg (hydrochloride) 15.1 Antiseptics 17.3 Anti-inflammatory medicines ■ sulfasalazine Retention enema ■ chlorhexidine Solution: 5% (digluconate) for dilution Suppository: 500 mg

■ ethanol Solution: 70% (denatured) Tablet: 500 mg

■ polyvidone iodine Solution: 10% Complementary List 15.2 Disinfectants ■ hydrocortisone Retention enema

■ chlorine base Powder: (0.1% available Suppository: 25 mg (acetate) compound chlorine) for solution (■ only applies to hydrocortisone retention enema). ■ chloroxylenol Solution: 4.8% 17.4 Laxatives glutaral Solution: 2% ■ senna Tablet: 7.5 mg (sennosides) 16. Diuretics (or traditional dosage forms) 17.5 Medicines used in diarrhoea amiloride Tablet: 5 mg (hydrochloride) 17.5.1 Oral rehydration ■ furosemide Injection: 10 mg/ml in 2-ml ampoule oral rehydration salts*

Tablet: 40 mg glucose: 75 mEq sodium: 75 mEq or mmol/l ■ hydrochlorothiazide Tablet (scored): 25 mg chloride: 65 mEq or mmol/l mannitol Injectable solution: 10%; 20% potassium: 20 mEq or mmol/l citrate: 10 mmol/l spironolactone Tablet: 25 mg osmolarity: 245 mOsm/l

glucose: 13.5 g/l 17. Gastrointestinal medicines sodium chloride: 2.6 g/l potassium chloride: 1.5 g/l 17.1 Antacids and other antiulcer trisodium citrate dihydrate+: 2.9 g/l medicines + trisodium citrate dihydrate may be replaced by aluminium hydroxide Oral liquid: 320 mg/5 ml sodium hydrogen carbonate (sodium bicarbonate) Tablet: 500 mg 2.5 g/l. However, as the stability of this latter formulation is very poor under tropical conditions, it is only ■ ranitidine Injection: 25 mg/ml in 2-ml ampoule recommended when manufactured for immediate use.

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* In cases of cholera, a higher concentration of 18.3.3 Intrauterine devices sodium may be required. copper-containing device 17.5.2 Medicines for diarrhoea in children 18.3.4 Barrier methods zinc sulfate* Oral liquid: in 10 mg per unit dosage forms condoms Tablet: in 10 mg diaphragms per unit dosage forms 18.3.5 Implantable contraceptives * In acute diarrhoea zinc sulfate should be used as an adjunct to oral rehydration salts. levonorgestrel-releasing Two-rod levonorgestrel- implant releasing implant, each 17.5.3 Antidiarrhoeal (symptomatic) medicines rod containing 75 mg of in adults levonorgestrel (150 mg total) codeine* Tablet: 30 mg (phosphate) 18.4 Estrogens * The role of this item has been questioned and its ■ ethinylestradiol* Tablet: 10 micrograms; continued inclusion on the list will be reviewed at the 50 micrograms next meeting of the Expert Committee. * The public health relevance and/or comparative efficacy and/or safety of this item has been questioned 18. Hormones, other endocrine and its continued inclusion on the list will be reviewed medicines and contraceptives at the next meeting of the Expert Committee. 18.1 Adrenal hormones and synthetic 18.5 Insulins and other antidiabetic agents substitutes glibenclamide Tablet: 2.5 mg; 5 mg Addison’s disease is a rare condition; adrenal insulin injection Injection: 40 IU/ml in 10-ml vial; hormones are already included in section 3. (soluble) 100 IU/ml in 10-ml vial 18.2 Androgens intermediate-acting Injection: 40 IU/ml in insulin 10-ml vial; 100 IU/ml Complementary List in 10-ml vial (as compound insulin zinc suspension testosterone Injection: 200 mg or isophane insulin) (enantate) in 1-ml ampoule metformin Tablet: 500 mg (hydrochloride) 18.3 Contraceptives 18.6 Ovulation inducers 18.3.1 Oral hormonal contraceptives Complementary List ■ ethinylestradiol + Tablet: 30 micrograms + ■ levonorgestrel 150 micrograms clomifene Tablet: 50 mg (citrate)

■ ethinylestradiol + Tablet: 35 micrograms + 18.7 Progestogens ■ norethisterone 1.0 mg norethisterone* Tablet: 5 mg levonorgestrel Tablet: 30 micrograms; 750 micrograms (pack of two); * The public health relevance and/or comparative ef- 1.5 mg ficacy and/or safety of this item has been questioned and its continued inclusion on the list will be reviewed 18.3.2 Injectable hormonal contraceptives at the next meeting of the Expert Committee. medroxyprogesterone Depot injection: Complementary List acetate 150 mg/ml in 1-ml vial medroxyprogesterone acetate* Tablet: 5 mg medroxyprogesterone acetate + Injection: estradiol cypionate 25 mg + 5 mg * The public health relevance and/or comparative efficacy and/or safety of this item has been questioned norethisterone enantate Oily solution: 200 mg/ml and its continued inclusion on the list will be reviewed in 1-ml ampoule at the next meeting of the Expert Committee.

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18.8 Thyroid hormones and antithyroid All vaccines should comply with the WHO Require- medicines ments for Biological Substances. BCG vaccine levothyroxine Tablet: 50 micrograms; 100 micrograms (sodium salt) cholera vaccine potassium iodide Tablet: 60 mg diphtheria vaccine ■ propylthiouracil Tablet: 50 mg hepatitis A vaccine 19. Immunologicals hepatitis B vaccine 19.1 Diagnostic agents Haemophilus influenzae type b vaccine influenza vaccine All tuberculins should comply with the WHO Require- ments for Tuberculins (Revised 1985). WHO Expert Japanese encephalitis vaccine Committee on Biological Standardization. Thirty-sixth report. (WHO Technical Report Series, No. 745, 1987, measles vaccine Annex 1). meningococcal meningitis vaccine tuberculin, purified protein Injection derivative (PPD) mumps vaccine 19.2 Sera and immunoglobulins pertussis vaccine

All plasma fractions should comply with the WHO pneumococcal vaccine Requirements for the Collection, Processing and poliomyelitis vaccine Quality Control of Blood, Blood Components and Plasma Derivatives (Revised 1992). WHO Expert rabies vaccine Committee on Biological Standardization. Forty-third report. (WHO Technical Report Series, No. 840, 1994, rotavirus vaccine Annex 2). rubella vaccine anti-D immunoglobulin Injection: 250 micrograms tetanus vaccine (human) in single-dose vial typhoid vaccine antitetanus immunoglobulin Injection: 500 IU (human) in vial varicella vaccine antivenom immunoglobulin* Injection yellow fever vaccine * Exact type to be defined locally. 20. Muscle relaxants diphtheria antitoxin Injection: 10 000 IU; (peripherally acting) and 20 000 IU in vial cholinesterase inhibitors ■ rabies immunoglobulin Injection: 150 IU/ ml in vial ■ alcuronium Injection: 5 mg (chloride)/ ml in 2-ml ampoule 19.3 Vaccines neostigmine Injection: 500 micrograms Selection of vaccines from the Model List will need to in 1-ml ampoule; 2.5 mg be determined by each country after consideration (metilsulfate) in 1-ml ampoule of international recommendations, epidemiology and national priorities. The list below details the vaccines Tablet: 15 mg (bromide) for which there is either a recommendation from the Strategic Advisory Group of Experts on Immuniza- suxamethonium Injection: 50 mg (chloride)/ tion (SAGE) (http://www.who.int/immunization/ ml in 2-ml ampoule sage_conclusions/en/index.html) and/or a WHO po- Powder for injection (chloride), in vial sition paper (http://www.who.int/immunization/documents/positionpapers/en/index.html). This site will be Complementary List updated as new position papers are published and contains the most recent information and recommen- pyridostigmine Injection: 1 mg in 1-ml ampoule dations.

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Tablet: 60 mg (bromide) mifepristone* Ð Tablet 200 mg Ð misoprostol * tablet 200 micrograms ■ vecuronium Powder for injection: 10 mg (bromide) in vial * Requires close medical supervision.

21. Ophthalmological Where permitted under national law preparations and where culturally acceptable.

This section will be reviewed at the next meeting of 22.2 Antioxytocics (tocolytics) the Expert Committee. nifedipine Immediate release capsule: 10 mg 21.1 Anti-infective agents 23. Peritoneal dialysis solution aciclovir Ointment: 3% W/W Complementary List ■ gentamicin* Solution (eye drops): 0.3% (sulfate) intraperitoneal dialysis solution Parenteral * Final selection depends on indication for use. (of appropriate composition) solution ■ tetracycline Eye ointment: 1% (hydrochloride) 24. Psychotherapeutic 21.2 Anti-inflammatory agents medicines ■ prednisolone Solution (eye drops): 0.5% (sodium phosphate) 24.1 Medicines used in psychotic disorders 21.3 Local anaesthetics ■ chlorpromazine Injection: 25 mg (hydro ■ tetracaine Solution (eye drops): chloride)/ml in 2-ml ampoule 0.5% (hydrochloride) Oral liquid: 25 mg (hydrochloride)/5 ml 21.4 Miotics and antiglaucoma medicines Tablet: 100 mg (hydrochloride) acetazolamide Tablet: 250 mg ■ fluphenazine Injection: 25 mg (decanoate ■ pilocarpine Solution (eye drops): 2%; or enantate) in 1-ml ampoule 4% (hydrochloride or nitrate) ■ haloperidol Injection: 5 mg in 1-ml ampoule ■ timolol Solution (eye drops): 0.25%; Tablet: 2 mg; 5 mg 0.5% (as maleate) 21.5 Mydriatics 24.2 Medicines used in mood disorders 24.2.1 Medicines used in depressive disorders atropine Solution (eye drops): 0.1%; 0.5%, 1% (sulfate) ■ amitriptyline Tablet: 25 mg (hydrochloride) Complementary List fluoxetine Capsule or tablet: 20 mg epinephrine Solution (eye drops): 2% (present as hydrochloride) (adrenaline) (as hydrochloride) 24.2.2 Medicines used in bipolar disorders

22. Oxytocics and antioxytocics carbamazepine Tablet (scored): 100 mg; 200 mg 22.1 Oxytocics lithium carbonate Capsule or tablet: 300 mg

■ ergometrine Injection: 200 micrograms valproic acid Tablet (enteric-coated): 200 mg; (hydrogen maleate) in 1-ml ampoule 500 mg (sodium valproate) oxytocin Injection: 10 IU in 1-ml ampoule 24.3 Medicines used in generalized Complementary List anxiety and sleep disorders misoprostol Vaginal tablet: 25 micrograms ■ diazepam Tablet (scored): 2 mg; 5 mg

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24.4 Medicines used for obsessive 26. Solutions correcting water, compulsive disorders and panic attacks electrolyte and acid-base clomipramine Capsule: 10 mg; 25 mg disturbances (hydrochloride) 26.1 Oral 24.5 Medicines used in substance dependence programmes oral rehydration salts See section 17.5.1 potassium chloride Powder for solution Complementary List

■ methadone* Concentrate for oral liquid: 26.2 Parenteral 5 mg/ml; 10 mg/ml (hydrochloride) glucose Injectable solution: 5%; Oral liquid: 5 mg/5 ml; 10 mg/5 ml 10% isotonic; 50% hypertonic

* The square box is added to include buprenorphine. glucose with Injectable solution: 4% glucose, The medicines should only be used within an estab- sodium chloride 0.18% sodium chloride + lished support programme. (equivalent to Na 30 mmol/l, Cl- 30 mmol/l)

25. Medicines acting on the potassium chloride Solution: 11.2% in respiratory tract 20-ml ampoule (equivalent to K+ 1.5 mmol/ml, 25.1 Antiasthmatic and medicines for Cl- 1.5 mmol/ml) chronic obstructive pulmonary disease sodium chloride Injectable solution: 0.9% isotonic (equivalent to Na+ 154 mmol/l, ■ beclometasone Inhalation (aerosol): Cl- 154 mmol/l 50 micrograms per dose (dipropionate); 250 micrograms sodium hydrogen Injectable solution: (dipropionate) per dose carbonate 1.4% isotonic (equivalent to Na+ 167 mmol/l, HCO - 167 mmol/l) epinephrine Injection: 1 mg (as hydrochloride 3 (adrenaline) or hydrogen tartrate) in Solution: 8.4% in 10-ml 1-ml ampoule ampoule (equivalent to Na+ 1000 mmol/l, HCO -1000 mmol/l) ipratropium bromide Inhalation (aerosol): 20 3 micrograms/metered dose ■ sodium lactate, Injectable solution compound solution ■ salbutamol Inhalation (aerosol): 100 micrograms (as sulfate) per dose 26.3 Miscellaneous

Injection: 50 micrograms (as water for injection 2-ml; 5-ml; 10-ml ampoules sulfate)/ml in 5-ml ampoule

Oral liquid: 2 mg/5 ml 27. Vitamins and minerals Respirator solution for use in nebulizers: ascorbic acid Tablet: 50 mg 5 mg (as sulfate)/ml ■ ergocalciferol Capsule or tablet: Tablet: 2 mg; 4 mg (as sulfate) 1.25 mg (50 000 IU) 25.2 Other medicines acting on the Oral liquid: 250 micrograms/ respiratory tract ml (10 000 IU/ml) iodine Capsule: 200 mg caffeine citrate Injection: 20 mg/ml (equivalent to 10 mg caffeine base/ml) Iodized oil: 1 ml (480 mg iodine); Oral liquid: 20 mg/ml (equivalent to 0.5 ml (240 mg iodine) in ampoule 10 mg caffeine base/ml) (oral or injectable); 0.57 ml (308 mg iodine) in dispenser bottle

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■ nicotinamide Tablet: 50 mg riboflavin Tablet: 5 mg pyridoxine Tablet: 25 mg (hydrochloride) sodium fluoride In any appropriate topical formulation retinol Capsule: 50 000 IU; 100 000 IU; 200 000 IU (as palmitate) thiamine Tablet: 50 mg (hydrochloride) Oral oily solution: 100 000 IU Complementary List (as palmitate)/ml in multidose dispenser calcium gluconate Injection: 100 mg/ml Tablet (sugar-coated): 10 000 IU (as palmitate) in 10-ml ampoule Water-miscible injection: 100 000 IU (as palmitate) in 2-ml ampoule

111 WHO Drug Information Vol 21, No. 2, 2007

Regulatory Action and News

Tegaserod: marketing placebo. Zelnorm¨ is a prescription suspension medication approved for short term treatment of women with irritable bowel Canada — Marketing and sales of syndrome with constipation and for tegaserod hydrogen maleate (Zelnorm¨) patients younger than 65 years with tablets have been suspended in Canada chronic constipation. to permit further evaluation of important safety information. Patients should contact their physician to discuss alternative treatments for their Zelnorm¨ is a serotonin 5-HT4 receptor condition. Physicians should work with partial agonist indicated for the sympto- their patients and transition them to other matic treatment of irritable bowel syn- therapies as appropriate to their symp- drome with constipation in female pa- toms and need. tients whose main symptoms are constipation and abdominal pain and/or dis- Thirteen patients treated with Zelnorm¨ comfort and for the treatment of chronic (0.1%) had serious and life-threatening idiopathic constipation in patients under cardiovascular side effects; among these, 65 years of age. four patients had a heart attack (one died), six had a type of severe heart chest A recent retrospective analysis of pooled pain which can quickly turn into a heart clinical trial data showed that the inci- attack, and three had a stroke. dence of cardiovascular ischemic events The FDA has indicated a willingness to (1) in patients taking Zelnorm¨ was consider limited re-introduction of higher than in those taking placebo: Zelnorm¨ at a later date if a population of patients can be identified in whom the Canadian pharmacists and distributors benefits of the drug outweigh the risks. have been requested to return the prod- However, before FDA makes a decision uct to the company. Patients should about limited re-introduction, any pro- discontinue treatment and contact their posed plan would be discussed at a physician for advice about alternative public advisory committee meeting. therapies. Reference: FDA Public Health Advisory, 30 Reference: Communication from Novartis March 2007 Pharmaceuticals Canada Inc. 30 March 2007 posted by Medeffect at http://www.hc-sc.gc.ca Pergolide: voluntary withdrawal of products United States of America — The Food and Drug Administration (FDA) has United States of America — The Food informed patients and health care prof- and Drug Administration (FDA) has essionals that tegaserod maleate announced that manufacturers of (Zelnorm¨) will no longer be marketed. A pergolide drug products, used to treat new safety analysis has found a higher Parkinson disease, will voluntarily remove chance of heart attack, stroke, and these drugs from the market because of worsening heart chest pain in patients the risk of serious damage to patients’ treated with tegaserod compared to heart valves. The products being with-

112 WHO Drug Information Vol 21, No. 2, 2007 Regulatory Action and News

drawn are Permax¨, the trade name for hyperproteinaemia disorders, a consider- pergolide, and two generic versions ably lower dose of Dostinex¨ is used.

Two new studies showed that patients Reference: FDA News, P07-54 and Public Health Advisory, 29 March 2007 at http:// with Parkinson disease who were treated www.fda.gov with pergolide had an increased chance of serious damage to their heart valves when compared to patients who did not Aliskiren approved for receive the drug. Pergolide is a dopamine hypertension agonist used with levodopa and carbidopa to manage the signs and symptoms United States of America — The Food of Parkinson disease. and Drug Administration (FDA) has announced the approval of aliskiren Healthcare professionals who prescribe (Tekturna¨) tablets for the treatment of pergolide should consider the following: hypertension. Aliskiren acts by inhibiting renin. ¥ If continued treatment is necessary, another dopamine agonist should be Effectiveness was demonstrated in six placebo-controlled eight-week clinical substituted for pergolide. There are other dopamine agonists approved for trials, which studied over 2000 patients the treatment of Parkinson disease that with mild to moderate hypertension. The effect was maintained for up to one year. are not associated with heart valve damage. Published transition regimens When used in combination with hydro- describe the conversion from one DA to chlorothiazide, further reductions in blood pressure were achieved. another. Aliskiren was effective across all demo- ¥ If treatment with a dopamine agonist is graphic subgroups, but African American to be discontinued, pergolide should not patients tended to have smaller reduc- be stopped abruptly, because rapid tions in blood pressure than Caucasians discontinuation of all dopamine agonist and Asians, as is generally true for drugs therapies can be dangerous. Instead, that affect the renin-angiotensin system. gradually decrease the dose of pergolide. Side effects were usually mild and brief. Diarrhoea was reported by approximately ¥ Patients who will be taken off pergolide 2 percent of patients on the higher of the should be told that other effective two approved doses, compared with options for treatment exist, including approximately 1 percent on placebo. three other dopamine agonists that are Rarely, patients developed an allergic not associated with damage to heart reaction with swelling of the face, lips or valves. tongue and difficulty breathing. This has been seen with other drugs for high blood One of the drugs included in the recent pressure that act directly on the renin- studies showing increased chance of angiotensin system. heart valve problems is cabergoline (Dostinex¨), another dopamine agonist. Aliskiren and other drugs that act directly This drug is approved in the US for the on the renin-angiotensin system should treatment of hyperproteinaemia disorders. not be used during pregnancy. Dostinex¨ is not approved in the US for Reference: FDA News, P07-38. 6 March 2007 the treatment of Parkinson disease. For at http://www.fda.gov

113 Regulatory Action and News WHO Drug Information Vol 21, No. 2, 2007

Lapatinib approved for levels of human tumour necrosis factor advanced breast cancer alpha, which plays an important role in abnormal inflammatory and immune United States of America —The Food responses. The labelling includes a and Drug Administration (FDA) has boxed warning about potential serious approved lapatinib (Tykerb ¨), a targeted adverse events. Adalimumab has been anti-cancer treatment to be used in studied in 1478 patients with Crohn combination with capectabine (Xeloda¨) disease in four clinical trials comparing for patients with advanced, metastatic the drug to a placebo and two longer term breast cancer that is HER2 positive. The extension studies. combination treatment is indicated for women who have received prior therapy Use of this product has been associated with other cancer drugs, including an with serious, sometimes fatal, infections, anthracycline, a taxane, and trastuzumab. including cases of tuberculosis, opportun- According to the American Cancer istic infections, and sepsis. Before initiat- Society, about 180 000 new cases of ing adalimumab treatment, patients breast cancer are diagnosed each year. should be evaluated for tuberculosis risk factors and tested for latent tuberculosis Lapatinib is a kinase inhibitor unlike, for infection. Other serious adverse events example, trastuzumab — a monoclonal reported by adalimumab users include antibody, which is a large protein mol- lymphoma. The most frequent adverse ecule that targets the part of the HER2 events included upper respiratory infec- protein on the outside of the cell. Be- tions, sinusitis, and nausea. cause of this difference in mechanism of action, Tykerb¨ works in some HER2 Humira¨ was previously approved for the positive breast cancers that are no longer treatment of three autoimmune diseases: benefiting from trastuzumab. rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Commonly reported side effects included diarrhoea, nausea, vomiting, rash and Reference: FDA News, P07-30. 27 February hand-foot syndrome which may include 2007 at http://www.fda.gov numbness, tingling, redness, swelling and discomfort of hands and feet. Generally Rapid test for meningitis reversible decreases in heart function cleared for marketing have also been reported in a small percentage of patients. United States of America — The Food and Drug Administration (FDA) has Reference: FDA News, P07-44, 13 March cleared for marketing a test that uses 2007 at http://www.fda.gov molecular biology to quickly detect the presence of viral meningitis. Adalimumab approved for Crohn disease The Xpert EV¨ test, when used in combination with other laboratory tests, will help United States of America — The Food physicians distinguish between viral and and Drug Administration (FDA) has bacterial meningitis. approved adalimumab (Humira¨) to treat adult patients with moderate to severe Meningitis is diagnosed by testing the Crohn disease. Adalimumab is a human- fluid obtained from a patient during a derived, genetically-engineered mono- spinal tap. Typically, diagnostic tests for clonal antibody to reduce excessive meningitis can take up to a week to get

114 WHO Drug Information Vol 21, No. 2, 2007 Regulatory Action and News

results. But results from the Xpert EV test designed to destroy bacteria and other are available in two and one-half hours. infection-causing organisms break these cells down. This leads to abnormally The accuracy of the Xpert EV¨ test was darkened urine and, more importantly, confirmed in a multi-site study at six causes anaemia. Depending upon the institutions. A total of 255 patient samples severity of the disorder, patients with PNH were tested and demonstrated that 96 may have pain, fatigue and debilitating percent of patients who tested positive weakness, the need for frequent blood did have viral meningitis, and that 97 transfusions, blood clots, and life-threat- percent of patients who tested negative ening or fatal strokes, heart attacks and did not have viral meningitis. intestinal disease.

Reference: FDA News, P07-46, 16 March Eculizumab does not cure PNH, but 2007 at http://www.fda.gov treats the breakdown of red blood cells, the most common characteristic of PNH. Eculizumab approved for Eculizumab blockade of the body’s natural immune system increases the paroxysmal nocturnal patient’s susceptibility to certain serious haemoglobinuria infections, particularly meningococcal United States of America —The Food infections. Serious meningococcal infec- and Drug Administration (FDA) has tion was the most important adverse approved eculizumab (Soliris¨), the first reaction experienced by patients in product for the treatment of paroxysmal clinical studies. Because of the high risk nocturnal haemoglobinuria (PNH), a rare for serious meningococcal infections, all type of blood disorder that can lead to 196 PNH patients in the clinical studies disability and premature death. were vaccinated with a meningococcal vaccine; two of them developed meningo- PNH, which usually develops in adults, is coccal sepsis. a disease characterized by red blood Reference: FDA News, P07-47, 16 March cells that develop abnormally. Once the 2007 at http://www.fda.gov abnormal cells are present in the blood- stream, naturally occurring proteins

115 WHO Drug Information Vol 21, No. 2, 2007

Access to Medicines

Neglected tropical diseases health and social and economic well- being of affected communities. One sixth of the world’s population suffer from one or more neglected tropical Reference: WHO Department of Control of diseases such as Buruli ulcer, cholera, Neglected Tropical Diseases at http:// cysticercosis, dracunculiasis (guinea- www.who.int/neglected_diseases/en/ worm disease), foodborne trematode index.html infections, such as fascioliasis, hydatido- sis, leishmaniasis, lymphatic filariasis, Open access database onchocerciasis, schistosomiasis, soil- for neglected medicines transmitted helminthiasis, trachoma and development trypanosomiasis, although there are other estimates that suggest the number could An international network of researchers be much higher. has announced the release of a new web-based resource designed to facilitate Several of these diseases are vector- the development of medicines to fight borne. Populations most affected are infectious diseases afflicting the often the poorest and most vulnerable developing world. The Drug Target and are in tropical and subtropical areas Prioritization Database is available at of the world. Some diseases affect in- http://TDRtargets.org. dividuals throughout their lives, causing a high degree of morbidity and physical The database is described as a compre- disability and, in certain cases, gross hensive set of information pertinent to disfigurement. Others are acute infec- drug target discovery, for a diverse tions, with transient, severe and some- array of parasitic and bacterial diseases. times fatal outcomes. The Drug Target Prioritization Network was established in 2005 by the Special For a large group of these diseases Ð Programme for Research and Training in mainly helminthic infections Ð effective, Tropical diseases (TDR) of WHO and inexpensive or donated drugs are avail- includes a global team of academic able for their prevention and control. laboratories, research centres and However, there is second group which industry scientists, focusing on the requires systematic case-finding and pathogens responsible for malaria, management at an early stage. Simple tuberculosis, African sleeping sickness, diagnostic tools and safe and effective leishmaniasis, Chagas disease and treatment regimens still need to be worm infections such as schistosomiasis developed for some of these diseases. and filariasis — all of which are For others, vector control is available, as in desperate need of new treatments. in the case of Chagas disease. Together, these diseases are responsible Increased awareness and advocacy are for billions of infections in the developing needed to draw attention to the realistic world and more than six million deaths prospect of reducing the negative impact per year. of neglected tropical diseases on the

116 WHO Drug Information Vol 21, No. 2, 2007 Access to Medicines

New avenues for drug discovery literature and other databases relevant to The database is unique in that it allows each putative drug target. The network any researcher — in both developed and has invested substantial effort in annota- developing countries — to have access to tion to assist scientists in the identification information on the complete genome of high-value drug targets. The database sequences for organisms responsible for also permits comments from experts in five tropical diseases, with more antici- the field. pated for the parasitic worms known as helminths. Pharmaceutical firms have User-defined weightings permit potential extensive libraries of chemicals that might drug targets to be ranked according to act against the disease pathogens. The their desirability, providing prioritized, missing step, which this initiative takes, is customized lists. While this network was to make available a list of proposed and developed to facilitate drug target identifi- validated drug targets, in addition to cation, it is also useful for the identifica- allowing users to define their own search tion of vaccine and diagnostic targets as criteria. This resource should expedite the well, and could spur fundamental re- time-consuming and high-risk early search into areas such as target valida- stages of drug development. tion, assay development, biomarkers and drug resistance. The TDRtargets.org web site combines available genomic and bioinformatic Reference: Special Programme for Research data for each priority organism with and Training in Tropical diseases (TDR) at automatically extracted and manually http://TDRtargets.org curated information from the research

117 WHO Drug Information Vol 21, No. 2, 2007

Consultation Document

International Pharmacopoeia

Artemether and lumefantrine capsules

Draft proposal for the International Pharmacopoeia (March 2007). Please address any comments to Quality Assurance and Safety: Medicines, Medi- cines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland. Fax: ++41 22 791 4730 or e-mail to [email protected]

Category. Antimalarial.

Storage. Artemether and Lumefantrine capsules should be kept in a well-closed container, protected from light.

Additional information. Strength in the current WHO Model List of Essential Medi- cines: 20 mg Artemether and 120 mg Lumefantrine.

[Note from the Secretariat: Artemether and Lumefantrine capsules are not included in the current WHO Model list of essential medicines, only tablets of above strength.]

REQUIREMENTS

Complies with the monograph for “Capsules”.

Artemether and Lumefantrine capsules contain Artemether and Lumefantrine. They contain not less than 90.0% and not more than 110.0% of the amounts of artemether

(C16H26O5) and lumefantrine (C30H32Cl3NO) stated on the label. Identity tests

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 40 volumes of light petroleum R1, 10 volumes of ethyl acetate R and 5 volumes of glacial acetic acid R as the mobile phase. Apply separately to the plate 10 µl of each of the following 2 solutions in acetone R. For solution (A) shake a quantity of the contents of the capsules equivalent to about 10 mg Artemether (about 60 mg Lumefantrine) for 5 minutes with 10 ml, filter, and use the clear filtrate. For solution (B) use 1 mg artemether RS and 6 mg lumefantrine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air.

118 WHO Drug Information Vol 21, No. 2, 2007 International Pharmacopoeia

(i) Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, and intensity to that obtained with solution B (identifying Lumefantrine).

(ii) Spray the plate with sulfuric acid/methanol TS. Heat the plate for 10 minutes at 140 ûC. Examine the chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity to that obtained with solution B (identifying Artemether).

A.2. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R5 as the coating substance and a mixture of 40 volumes of light petroleum R1, 10 volumes of ethyl acetate R and 5 volumes of glacial acetic acid R as the mobile phase. Apply separately to the plate 10 µl of each of the following 2 solutions in acetone R. For solution (A) shake a quantity of the contents of the capsules equivalent to about 10 mg Artemether (about 60 mg Lumefantrine) for 5 minutes with 10 ml, filter, and use the clear filtrate. For solution (B) use 1 mg artemether RS and 6 mg lumefantrine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Spray with sulfuric acid/methanol TS. Heat the plate for 10 minutes at 140ûC, allow it to cool and expose to iodine vapours for 20 minutes. Examine the chromatogram immediately in daylight.

The principal spots obtained with solution A corresponds in position, appearance, and intensity to those obtained with solution B.

B. See the test described below under Assay. The retention times of the two principal peaks in the chromatogram obtained with solution (1) are similar to those in the chromatogram obtained with solution (2).

Artemether-related substances. Protect samples from light, also during chromatography.

Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R5 as the coating substance and a mixture of 40 volumes of light petroleum R1, 10 volumes of ethyl acetate R and 5 volumes of glacial acetic acid R as the mobile phase.

Prepare the following solutions in the solvent consisting of 1 volume of purified water and 1 volume of acetonitrile R. For solution (1), weigh and mix the contents of 20 capsules. To a quantity of the powder containing 100 mg of artemether add 20 ml of the solvent, sonicate for 15 minutes and centrifuge. Filter a portion of the supernatant through a 0.45 µm filter, discarding the first few ml of the filtered solution. For solution (2) dissolve 2 mg of each of artemether RS, dihydroartemisinin (artenimol RS) and á- artemether RS in 20 ml of the solvent. For solution (3) dilute 2.0 ml of solution (2) to 20 ml with the solvent. For solution (4) dilute 3.0 ml of solution (2) to 20 ml with the solvent. For solution (5) dilute 5.0 ml of solution (2) to 20 ml with the solvent. For solution (6) dilute 1.0 ml of solution (2) to 2 ml with the solvent. For solution (7) dilute 3.0 ml of solution (2) to 4 ml with the solvent.

119 International Pharmacopoeia WHO Drug Information Vol 21, No. 2, 2007

Apply separately to the plate 20 µl of each of the solution (1), (3), (4), (5), (6) and (7). After application allow the spots to dry for 15 minutes in a current of cool air. Develop over a path of 12 cm. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Dip the plate in sulfuric acid/ methanol TS. Heat the plate for 10 minutes at 140 ûC. Examine the chromatogram in daylight.

Artemether and related substances have the following Rf values: impurity A about 0.25; dihydroartemisinin about 0.3; impurity B about 0.35; α-artemether about 0.4; artemether about 0.55.

In the chromatogram obtained with solution (1):

Ðany spot corresponding in Rf value to impurity A is not more intense than the spot corresponding to artemether obtained with solution (7) (1.5%);

Ðany spot corresponding in Rf value to dihydroartemisinin is not more intense than the spot corresponding to dihydroartemisinin obtained with solution (6) (1.0%);

Ðany spot corresponding in Rf value to impurity B is not more intense than the spot corresponding to artemether obtained with solution (5) (0.5%);

Ðany spot corresponding in Rf value to á-artemether is not more intense than the spot corresponding to á-artemether obtained with solution (4) (0.3%);

Ðthe spot of any other impurity is not more intense than the spot corresponding to artemether obtained with solution (3) (0.2%). Disregard any spot remaining at the point of application.

Assay. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (15 cm x 3.9 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 ìm) (1 Symmetry is suitable.)

Use the following conditions for gradient elution:

Mobile phase A: 700 volumes of ion pair reagent and 300 volumes of acetonitrile R.

Mobile phase B: 300 volumes of ion pair reagent and 700 volumes of acetonitrile R.

Prepare the ion pair reagent by dissolving 5.65 g of sodium hexanesulfonate R and 2.75 g of sodium dihydrogen phosphate R in about 900 ml of purified water. Adjust the pH to 2.3 using phosphoric acid (~105 g/l) TS, dilute to 1000 ml and filter through a 0.45 µm filter.

120 WHO Drug Information Vol 21, No. 2, 2007 International Pharmacopoeia

Time Mobile phase A Mobile phase B Comments (min) (% v/v) (% v/v)

0Ð28 60 40 Isocratic 28Ð29 60 to 0 40 to 100 Linear gradient 29Ð45 0 100 Isocratic 45Ð46 0 to 60 100 to 40 Linear gradient 46Ð55 60 40 Isocratic re-equilibration

Prepare the following solutions in the solvent which is obtained by mixing 200 ml of ion pair reagent, 60 ml of purified water and 200 ml of 1-propanol R and diluting to 1000 ml with acetonitrile R. For solution (1), weigh and mix the contents of 20 capsules. Transfer a quantity of the powder containing about 20 mg of artemether (about 120 mg of lumefantrine), accurately weighed, to a 100 ml volumetric flask. Add approximately 85 ml of the solvent, sonicate for 20 minutes, allow to cool to room temperature and dilute to volume with the solvent. Filter through a 0.45 µm filter, discarding the first few ml of the filtered solution. For solution (2), accurately weigh 20 mg artemether RS and 120 mg lumefantrine RS in a 100 ml volumetric flask. Add approximately 85 ml of solvent, sonicate until dissolved, allow to cool to room temperature and dilute to volume.

Operate with a flow rate of 1.3 ml per minute. As a detector use an ultraviolet spectro- photometer set at a wavelength of about 210 nm for the first 28 minutes and then switch to about 380 nm.

Inject alternately 20 µl each of solutions (1) and (2). (The peak for artemether is eluted at a retention time of approximately 19 minutes, and that for lumefantrine at a retention time of approximately 34 minutes.)

Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of artemether (C16H26O5) and lumefantrine (C30H32Cl3NO). Impurities (artemether-related)

Dihydroartemisinin 284.4 C15H24O5

121 International Pharmacopoeia WHO Drug Information Vol 21, No. 2, 2007

α-artemether 298.4 C16H26O5

B. 298.4 C16H26O5

A. 238.3 C14H22O3

[Names to be provided for A and B]

122 WHO Drug Information Vol 21, No. 2, 2007 International Pharmacopoeia

Magnesi sulfatis injectio Magnesium sulfate Injection

Note from the Secretariat: Inclusion of a monograph for magnesium sulfate injection is considered advisable in view of the potential for errors in dosage due to confusion concerning the strength of this injection since “Magnesium sulfate” is the heptahydrate (mol wt 246.5 compared with 120 for anhydrous substance). This injection is included in the WHO Model List of Essential Medicines and within the “Making Pregnancy Safer” programme of the Family and Community Health cluster of WHO.

Description. A clear, colourless solution.

Category. Used in the prevention of seizures in eclampsia and pre-eclampsia.

Labelling. The designation of the container of Magnesium sulfate injection should indicate the quantity in terms of the amount of magnesium sulfate heptahydrate and as the approximate concentration of magnesium ions (Mg2+) in millimoles per ml.

Additional information. Strength in the current WHO Model list of essential medicines: 500 mg of magnesium heptahydrate /ml; the concentration of magnesium ions (Mg2+) is approximately 2 millimoles per ml (2 mmolMg2+/ml).

REQUIREMENTS Complies with the monograph for “Parenteral Preparations”.

Definition. Magnesium sulfate injection is a sterile solution of Magnesium Sulfate Heptahydrate in water for injections. The solution is sterilized by “Heating in an Auto- clave” or by another suitable method (see 5.8 Methods of Sterilization).

Magnesium sulfate injection contains not less than 90.0% and not more than 110.0% of the amount of MgSO4,7H2O stated on the label. Identity tests A. Dilute the injection to give a solution containing 5 mg of magnesium sulfate heptahydrate per ml. To 2 ml of this solution, add 1 ml of ammonia (100g/l) TS; a white precipitate is produced which redissolves after adding 1 ml of ammonium chloride (100g/l) TS. Add 1 ml of disodium hydrogen phosphate (40g/l) TS; a white, fine crystalline precipitate is formed.

B. Dilute the injection to give a solution containing 20 mg of magnesium sulfate heptahydrate per ml; yields reaction A described under 2.1 General identification tests as characteristic of sulfates.

123 International Pharmacopoeia WHO Drug Information Vol 21, No. 2, 2007

pH value. (1.13) pH of the injection, diluted if necessary to contain 500 mg of magnesium sulfate heptahydrate /ml: 5.5 - 7.0.

Assay. Dilute an accurately measured volume of the injection containing about 0.50 g of magnesium sulfate heptahydrate to 100 ml with water R and proceed with the titration as described under 2.5 Complexometric titrations for magnesium. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 12.32 mg of MGSO4, 7H2O

Zinci sulfas Zinc sulfate

Zinc sulfate monohydrate Zinc sulfate heptahydrate

Note from the Secretariat: Preparation of the zinc monographs was initiated because zinc supplementation is included in the revised the WHO/UNICEF recommendations for the management of diarrhoea as an adjunct to oral rehydration therapy.]

ZnSO4,H2O (monohydrate); ZnSO4,7H2O (heptahydrate) Relative molecular mass. 179.5 (monohydrate); 287.5 (heptahydrate).

Chemical name. Zinc sulfate monohydrate; CAS Reg. No. 7446-19-7 (monohydrate). Zinc sulfate heptahydrate; CAS Reg. No. 7446-20-0 (heptahydrate).

Description. A white or almost white, crystalline powder, or colourless, transparent crystals.

Solubility. Very soluble in water, practically insoluble in ethanol (~750 g/l) TS.

Category. Adjunct to oral rehydration salts in( prevention and) treatment of dehydra- tion due to diarrhoea; astringent.

Storage. Zinc sulfate should be kept in a well-closed non-metallic container.

REQUIREMENTS

Definition. Zinc sulfate monohydrate contains not less than 99.0% and not more than

101.0% of ZnSO4,H2O. Zinc sulfate heptahydrate contains not less than 99.0% and not more than 104.0% of ZnSO4,7H2O.

124 WHO Drug Information Vol 21, No. 2, 2007 International Pharmacopoeia

Identity tests

A. Dissolve 0.25 g in 5 ml of water R and add 0.2 ml of sodium hydroxide (400 g/l) TS. A white precipitate is formed. Add a further 2 ml of sodium hydroxide (400 g/l) TS. The precipitate dissolves. Add 10 ml of ammonium chloride (100 g/l) TS. The solution remains clear. Add 0.1 ml of sodium sulfite TS. A flocculent white precipitate is formed.

B. A 50 mg/ml solution yields the reactions described under 2.1 General identification tests as characteristic of sulfates.

C. The test substance complies with the limits of the assay. pH value. (1.13) pH of a 50 mg/ml solution in carbon-dioxide-free water R, 4.4-5.6.

Chlorides. Use 0.83 g in 20 ml for the preparation of the test solution as described under 2.2.1 Limit test for chlorides; not more than 300 ìg/g.

Iron. Use 0.40 g for the preparation of the test solution as described under 2.2.4 Limit test for iron; not more than 100 ìg/g.

Assay

For the monohydrate Dissolve about 80 mg, accurately weighed, in 5 ml of acetic acid (~120 g/l) TS and proceed with the titration as described under 2.5 Complexometric titrations for zinc. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 8.975 mg of ZnSO4,H2O. For the heptahydrate Dissolve about 0.13 g, accurately weighed, in 5 ml of acetic acid (~120 g/l) TS and proceed with the titration as described under 2.5 Complexometric titrations for zinc. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 1.438 g of ZnSO4,7H2O.

Paediatric zinc sulfate tablets

Note from the Secretariat: The term “paediatric” has been used in the title of this monograph since these tablets are included in the WHO Model List of Essential Medicines (revised March 2005) under “medicines for diarrhoea in children” (section17.5.2).

Preparation of the zinc monographs was initiated because zinc supplementation is included in the revised the WHO/UNICEF recommendations for the management of diarrhoea as an adjunct to oral rehydration therapy.

125 International Pharmacopoeia WHO Drug Information Vol 21, No. 2, 2007

Category. Adjunct to oral rehydration salts in (prevention and) treatment of dehydra- tion due to diarrhoea.

Storage. Paediatric zinc sulfate tablets should be kept in a well-closed container.

Labelling. The designation of the container of Paediatric zinc sulfate tablets should state that the active ingredient is in the monohydrate form and indicate the quantity in terms of the equivalent amount of elemental zinc.

Additional information. Strength in the current WHO Model list of essential medicines: 10 mg of elemental zinc (as zinc sulfate monohydrate).

REQUIREMENTS

Comply with the monograph for “Tablets”.

Definition. Paediatric zinc sulfate tablets contain Zinc Sulfate as the monohydrate in a suitable dispersible basis that may contain suitable flavouring agents. They contain not less than 90.0% and not more than 110.0% of the amount of zinc stated on the label.

Manufacture. The formulation of the tablets and the manufacturing process are designed and controlled so as to ensure that the metallic taste of the zinc salt is adequately masked.

Identity tests. For solution (A) shake a quantity of the powdered tablets containing the equivalent of 100 mg of zinc with 20 ml, filter, and use the clear filtrate.

A. To 5 ml of solution (A) add 0.2 ml of sodium hydroxide (400 g/l) TS. A white precipitate is formed. Add a further 2 ml of sodium hydroxide (400 g/l) TS. The precipitate dissolves. Add 10 ml of ammonium chloride (100 g/l) TS. The solution remains clear. Add 0.1 ml of sodium sulfite TS. A flocculent white precipitate is formed.

B. Five ml of solution (A) yields reaction A described under 2.1 General identification tests as characteristic of sulfates.

Disintegration. Comply with 5.4 Disintegration test for tablets and capsules, operat- ing the apparatus for 60 seconds.

Assay. Weigh and powder 20 tablets. To a quantity of the powder equivalent to about 29 mg of zinc, accurately weighed, add 5 ml of acetic acid (~120 g/l), sonicate for 15 minutes and add about 50 ml water R. Proceed with the titration as described under 2.5 Complexometric titrations for zinc. Each ml of disodium edetate (0.05 mol/l) VS is equivalent to 3.27 mg of zinc.

126 WHO Drug Information Vol 21, No. 2, 2007 International Pharmacopoeia

Paediatric zinc sulfate oral solution

Category. Adjunct to oral rehydration salts in (prevention and) treatment of dehydra- tion due to diarrhoea.

Storage. Paediatric zinc sulfate oral solution should be kept in a well-closed container.

Labelling. The designation of the container of Paediatric zinc sulfate oral solution should indicate the quantity in terms of the equivalent amount of elemental zinc.

Additional information. Strength in the current WHO Model list of essential medicines: 10 mg of zinc (as zinc sulfate) per 5 ml.

REQUIREMENTS

Complies with the monograph for “Liquids for Oral Use”.

Definition. Paediatric zinc sulfate oral solution is a solution of Zinc Sulfate as the monohydrate or heptahydrate in a suitable flavoured vehicle. It contains not less than 90.0% and not more than 110.0% of the amount of zinc stated on the label.

Manufacture. The formulation of the oral solution and the manufacturing process are designed and controlled so as to ensure that the metallic taste of the zinc salt is adequately masked.

Identity tests

A. To 5 ml add 0.2 ml of sodium hydroxide (400 g/l) TS. A white precipitate is formed. Add a further 2 ml of sodium hydroxide (400 g/l) TS. The precipitate dissolves. Add 10 ml of ammonium chloride (100 g/l) TS. The solution remains clear. Add 0.1 ml of sodium sulfite TS. A flocculent white precipitate is formed.

B. Five ml yields reaction A described under 2.1 General identification tests as characteristic of sulfates.

127 International Pharmacopoeia WHO Drug Information Vol 21, No. 2, 2007

pH value. (1.13) pH of the oral solution: 2.5Ð4.5.

Relative density

Note from the Secretariat: Comment is invited as to whether inclusion of a requirement for relative density is advisable and, if so, what limits would be considered suitable using method 1.3 of Ph. Int. (20 ûC).

Assay. To a quantity of the oral solution equivalent to about 10 mg of zinc, accurately measured, add 50 ml of purified water and 5 ml of ammonia buffer TS and titrate with disodium edetate (0.01 mol/l) VS using Mordant Black 11 indicator mixture R as indicator. Each ml of disodium edetate (0.01 mol/l) VS is equivalent to 0.6539 mg of zinc.

128 WHO Drug Information Vol 21, No. 2, 2007 Recent Publications, Information and Events

Informed consent for research Technological and financial resources are in resource-poor settings also necessary to build capacity for local collaborators and communities to ensure Ethical challenges in study design and that results of research are integrated into informed consent for health research in existing health systems. This requires resource-poor settings considers ethical collaborative efforts and engaged com- challenges to research design and mitment on the part of investigators, informed consent in biomedical and funding agencies, policy-makers, govern- behavioural studies conducted in re- mental institutions, and industry. source-poor settings. A review of the literature explores relevant social, cul- Reference: Ethical tural, and ethical issues in the conduct of challenges in study biomedical and social health research in design and informed developing countries. Ten case vignettes consent for health illustrate ethical challenges that arise in research in re- international research with culturally source-poor settings http:// www.who.int/ diverse populations. tdr/publications/ publications/ Professional and public debates concern- seb_topic5.htm ing the application of guidelines for ethical conduct in studies carried out in UNDP/WorldBank/ developing countries are likely to continue WHO-TDR http:// as new information becomes available. www.who.int/tdr/ Researchers in biomedicine, public topmenu/news/ health, and the social and behavioural sciences confront the challenging task of Lessons learned in home adhering to national and international management of malaria regulations in social and cultural environ- Implementation research in four ments in which ethical guidelines may not African countries be easily translated or applied. Increased awareness of ethical concerns associated Studies on treatment-seeking behaviour with study design and informed consent have shown that most malaria episodes among researchers working in resource- are first treated at home using shop- poor settings is needed. But strengthen- bought drugs. Part of the reason for this ing professional knowledge about interna- is poor access to formal health services. tional research ethics is not enough. These treatments may be incorrect or Investigators also require practical advice suboptimal. Since the majority of children on the best methods or models for who die from malaria do so within 48 articulating ethical guidelines in the field. hours of onset of illness, the early use of Empirical research on a wide range of effective antimalaria medicines close to issues relevant to the application of the home can help to reduce the burden ethical guidelines is needed, including of the disease in sub-Saharan Africa and studies of macro social and economic minimize the life-threatening conse- developments that drive the globalization quences of treatment delays. of the biomedical research enterprise.

129 Recent Publications, Information and Events WHO Drug Information Vol 21, No. 2, 2007

This guide focuses in particular on four Reference: FIP pharmacy information section countries Ð Burkina Faso, Ghana, Nigeria newsletter. March 2007 www.fip.org and Uganda Ð where country teams have completed community based studies in First-in-man clinical trials home management of malaria. for high risk products Reference: World European Union — The Committee for Health Organiza- Medicinal Products for Human Use tion. Lessons (CHMP) has adapted a draft guideline for learned in Home first-in-man clinical trials for potential Management of Malaria. Imple- high-risk medicinal products. This guide- mentation re- line has been prepared as one of the search in four measures for minimizing the risk of African countries, serious adverse reactions of the nature 2007 that occurred during the first-in-man clinical trials of TGN1412 (gene therapy). It gives guidance on managing the Developing drug information transition from non-clinical studies to first centres in India tests in humans for high-risk medicinal products. The draft guideline has been A unique training workshop was organ- released for a two-month public consulta- ized in Bangalore in December 2006. tion. Participants from India were provided with an introduction to drug information Reference: Press Release. EMEA, 26 March practice and rational drug use. The 2007. http://www.emea.europa.eu course was a part of a programme to expand the influence of the drug informa- Pakistan Pharmacists Society tion centres and clinical pharmacy train- discussion forum ing programmes which have developed in the south of India over the last ten years. The Pakistan Pharmacists Society promotes and expands the profession of The current programme is being coordi- pharmacy and the role of pharmacists. In nated by the Karnataka State Pharmacy order to improve drug use and pharmacy Council (KSPC) and is funded by WHO practice in the country, the Society has (India Office). KSPC established a drug launched a website to serve as an online information centre in 1997 and also works source of news, pharmacy jobs, and to with hospital-based clinical pharmacy provde an opportunity for pharmacists to training programs in Bangalore. Other link up, share ideas and develop activities departments of pharmacy practice in of interest. south India include drug information training in their clinical programs and offer Reference: Pakistan Pharmacists Society (PPS) http:// www.pharmacist.pk and http:// independent information to clinicians www. pharmacy.org.pk within their institutions. The centres will provide information to New quality assurance healthcare professionals and the public, compendium and will collect reports of suspected adverse drug reactions. Limited funding Over the years, WHO’s Expert Committee will be provided to purchase information on Specifications for Pharmaceutical resources but long-term support will be Preparations has made numerous required at the state level. recommendations to establish standards

130 WHO Drug Information Vol 21, No. 2, 2007 Recent Publications, Information and Events

and guidelines and to promote the 4. Inspection effective functioning of national regulatory and control systems and implementation ¥ Pre-approval inspections of internationally agreed standards. ¥ Inspection of pharmaceutical manufac- Many of the relevant documents en- turers dorsed by the Expert Committee are ¥ Inspection of drug distribution channels reproduced in a recently published compendium of guidelines and related ¥ Quality systems requirements for materials Quality Assurance of Pharma- national good manufacturingbpractice ceuticals. Second Edition aiming to inspectorates provide information covering all aspects ¥ Guidance on good manufacturing of WHO good manufacturing practices practices: inspection report and inspection. The compendium includes. ¥ Model certificate of good manufacturing practices 1. WHO good manufacturing practices: main principles for pharmaceutical 5. Hazard and risk analysis in pharma- products ceutical products

¥ Quality management in the drug indus- ¥ Application of hazard analysis and try: philosophy and essential elements critical control point (HACCP) methodol- ogy to pharmaceuticals ¥ Heating Ventilation and air-conditioning systems for non-sterile pharmaceutical 6. Sampling operations dosage forms ¥ Validation ¥ Sampling of pharmaceutical products and related materials ¥ Water for pharmaceutical use Reference: Quality Assurance of Pharmaceu- 2. WHO good manufacturing practices: ticals. Second Edition. http://www.who.int/ starting materials bookorders ¥ Active pharmaceutical ingredients (bulk drug substances) Pharmacological management of human H5N1 infection ¥ Pharmaceutical excipients The recent geographical spread of highly 3. WHO good manufacturing practices: pathogenic avian influenza A virus in specific pharmaceutical products poultry and wild waterfowl has increased opportunities for transmission of the ¥ Sterile pharmaceutical products H5N1 virus to humans. Outbreaks in poultry have now been accompanied by ¥ Biological products human cases in nine countries. To date, ¥ Investigational pharmaceutical products human cases have remained rare and for clinical trials in humans sporadic, but the disease is very severe and the case fatality is high. With the ¥ The manufacture of herbal medicines H5N1 virus now confirmed in birds in more than 50 countries, additional spo- ¥ Radiopharmaceutical products radic human cases should be anticipated.

131 Recent Publications, Information and Events WHO Drug Information Vol 21, No. 2, 2007

Although international experts agree that current pre-pandemic situation. Recom- antiviral drugs should be considered for mendations were based on careful treatment of H5N1 patients and also for consideration of the benefits, harms, chemoprophylaxis, the efficacy and burdens and cost of interventions. Risk effectiveness of these management categorizations for exposure were devel- options have not been systematically oped to assist countries in prioritizing the assessed. Guidance on their use is use of antiviral drugs where their needed worldwide. availability is limited.

In March 2006, the World Health Organi- Overall, the quality of the underlying zation (WHO) convened an international evidence for all recommendations was panel of clinicians experienced in the very low. No data from controlled clinical treatment of H5N1 patients, infectious trials of H5N1 infection are available. The disease experts, public health officers existing evidence is based on small and methodologists to develop rapid observational case series of H5N1 advice for the pharmacological manage- patients, results from in vitro and animal ment of patients with H5N1 infection. To model studies of H5N1, or the extrapola- develop evidence-based guidelines, the tion of data from high quality studies panel used a transparent methodological conducted to evaluate the treatment and guideline process, based on the GRADE chemoprophylaxis of normal, or “sea- approach, that included evaluation of sonal”, influenza. These shortcomings existing systematic reviews, literature highlight the need for further research. searches and expert consultation. The While the quality of the evidence for some resulting guidelines separate strong from of the critical outcomes was moderate or weak recommendations for or against a low, the overall quality of evidence on specific action and assign four categories which to base a summary assessment of quality of evidence (high, moderate, was very low for all antiviral drugs. low and very low). Differences exist in the quality of evidence for individual critical outcomes The panel considered several different among the various antiviral drugs (annex specific patient and exposure groups and 3 sets out the gradings and ratings). made a number of strong recommenda- Reference: World Health Organization. WHO tions for or against specific actions Rapid Advice Guidelines on pharmacological regarding the treatment and chemo- management of humans infected with avian prophylaxis of H5N1 virus infection. All influenza A (H5N1) virus. WHO/PSM/PAR/ recommendations are specific to the 2006 at http://www.who.int/medicines

132 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

International Nonproprietary Names for Pharmaceutical Substances (INN)

Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.

Lists of Proposed (1–96) and Recommended (1–57) International Nonproprietary Names can be found in Cumulative List No. 12, 2007 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie.

On trouvera d'autres listes de Dénominations communes internationales proposées (1–96) et recommandées (1–57) dans la Liste récapitulative No. 12, 2007 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.

Las listas de Denominaciones Comunes Internacionales Propuestas (1–96) y Recomendadas (1–57) se encuentran reunidas en Cumulative List No. 12, 2007 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

133

Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

Proposed International Nonproprietary Names: List 97 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 97 Proposed INN not later than 31st of October 2007. Publication date: 25th of June 2007

Dénominations communes internationales proposées: Liste 97 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 97 de DCI Proposées le 31 octobre 2007 au plus tard. Date de Publication: 25 juin 2007

Denominaciones Comunes Internacionales Propuestas: Lista 97 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 97 de DCI Propuestas el 31 de Octubre de 2007 a más tardar. Fecha de publicación: el 25 de Juno de 2007.

Proposed INN Chemical name or description: Action and use: Molecular formula (Latin, English, French, Spanish) Chemical Abstracts Service (CAS) registry number: Graphic formula

DCI Proposée Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS: Formule développée

DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula molecular Número de registro del CAS: Fórmula desarrollada

alaninati brivanibum brivanib alaninate (2R)-1-({4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo [2,1-f][1,2,4]triazin-6-yl}oxy)propan-2-yl L-alaninate angiogenesis inhibitor

alaninate de brivanib L-alaninate de (2R)-1-({4-[(4-fluoro-2-méthyl-1H-indol-5-yl)oxy]- 5-méthylpyrrolo[2,1-f][1,2,4]triazin-6-yl}oxy)propan-2-yle inhibiteur de l'angiogénèse

alaninato de brivanib L-alaninato de (2R)-1-({4-[(4-fluoro-2-metil-1H-indol-5-il)oxi]- 5-metilpirrolo[2,1-f][1,2,4]triazin-6-il}oxi)propan-2-ilo inhibidor de la angiogénesis

C22H24FN5O4 649735-63-7

N N N HCH3 O H2N O O NH O H CH3 CH3 F CH3

134 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

albiglutidum* albiglutide ([8-glycine]human glucagon-like peptide 1-(7-36)-peptidyl) ([8-glycine]human glucagon-like peptide 1-(7-36)-peptidyl)(human serum albumin (585 residues)) antidiabetic

albiglutide ([8-glycine]peptide 1 analogue au glucagon humain-(7-36)- peptidyl)([8-glycine]peptide 1 analogue au glucagon humain-(7-36)- peptidyl)(albumine sérique humaine (585 aminoacides)) antidiabétique

albiglutida ([8-glicina]péptido1 análogo al glucagón humano-(7-36)-peptidil) ([8-glicina]péptido 1 análogo al glucagón humano-(7-36)- peptidil)(albumina séria humana (585 aminoácidos)) antidiabético

C3232H5032N864O979S41 782500-75-8

HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR HGEGTFTSDV SSYLEGQAAK 50 EFIAWLVKGR DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV 100 KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC 150 CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY 200 EIARRHPYFY APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK 250 ASSAKQRLKC ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK 300 VHTECCHGDL LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI 350 AEVENDEMPA DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD 400 YSVVLLLRLA KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ 450 NCELFEQLGE YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH 500 PEAKRMPCAE DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA 550 LEVDETYVPK EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT 600 KEQLKAVMDD FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGL 645

Disulfide bridges location Position des ponts disulfure / Posiciones de los puentes disulfuro 113-122 135-151 150-161 184-229 228-237 260-306 305-313 325-339 338-349 376-421 420-429 452-498 497-508 521-537 536-547 574-619 618-627

albinterferonum alfa-2b* albinterferon alfa-2b human serum albumin (585 residues) fusion protein with human interferon α-2b (165 residues) antiviral

albinterféron alfa-2b protéine de fusion entre l’albumine sérique humaine (585 aminoacides) et l'interféron α-2b humain (165 aminoacides) antiviral

albinterferón alfa 2b proteína de fusión entre la albumina sérica humana (585 aminoácidos) y el interferón α-2b humano (165 aminoácidos) antiviral

135 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

C3796H5937N1015O1143S50 472960-22-8

DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA 50 KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE 100 CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY 150 APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAKQRLKC 200 ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK VHTECCHGDL 250 LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI AEVENDEMPA 300 DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA 350 KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ NCELFEQLGE 400 YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH PEAKRMPCAE 450 DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK 500 EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD 550 FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGLCDLPQ THSLGSRRTL 600 MLLAQMRRIS LFSCLKDRHD FGFPQEEFGN QFQKAETIPV LHEMIQQIFN 650 LFSTKDSSAA WDETLLDKFY TELYQQLNDL EACVIQGVGV TETPLMKEDS 700 ILAVRKYFQR ITLYLKEKKY SPCAWEVVRA EIMRSFSLST NLQESLRSKE 750

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro

53-62 75-91 90-101 124-169 168-177 200-246 245-253 265-279 278-289 316-361 360-369 392-438 437-448 461-477 476-487 514-559 558-567 586-683 614-723

Glycosylation sites : N-318 T-691

anamorelinum anamorelin (3R)-3-benzyl-N,N',N'-trimethyl-1-(2-methylalanyl-D-tryptophyl)= piperidine-3-carbohydrazide growth hormone-releasing factor

anamoréline (3R)-3-benzyl-N,N',N'-triméthyl-1-(2-méthylalanyl-D-tryptophyl)= pipéridine-3-carbohydrazide facteur de libération de l'hormone de croissance

anamorelina (3R)-3-bencil-N,N',N'-trimetil-1-(2-metilalanil-D-triptofil)piperidina- 3-carbohidrazida factor estimulante de la liberación de la hormona del crecimiento

C31H42N6O3 249921-19-5

H C CH O O CH3 3 3 H N N H2N N N CH3 H O CH3

apremilastum apremilast N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethyl]- 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide antiasthmatic

aprémilast N-{2-[(1S)-1-(3-éthoxy-4-méthoxyphényl)-2-(méthanesulfonyl)éthyl]- 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acétamide antiasthmatique

apremilast N-{2-[(1S)-1-(3-etoxy-4-metoxifenil)-2-(metansulfonil)etil]-1,3-dioxo- 2,3-dihidro-1H-isoindol-4-il}acetamida antiasmático

136 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C22H24N2O7S 608141-41-9

OO O S CH3 H N

CH3 O O H3C NH

O OCH3

arbaclofenum placarbilum arbaclofen placarbil (3R)-3-(4-chlorophenyl)-4-[({(1S)-2-methyl-1-[(2-methylpropanoyl)= oxy]propoxy}carbonyl)amino]butanoic acid antispasmodic

arbaclofène placarbil acide (3R)-3-(4-chlorophényl)-4-[({(1S)-2-méthyl- 1-[(2-méthylpropanoyl)oxy]propoxy}carbonyl)amino]butanoïque antispasmodique

arbaclofeno placarbilo ácido (3R)-3-(4-clorofenil)-4-[({(1S)-2-metil-1-[(2-metilpropanoil)oxi]= propoxi}carbonil)amino]butanoico antiespasmódico

C19H26ClNO6 847353-30-4

H3C CH3 O O H H3C O O N CO2H H H CH3

arterolanum arterolane N-(2-amino-2-methylpropyl)-2-{cis-dispiro[adamantane- 2,3'-[1,2,4]trioxolane-5',1"-cyclohexan]-4"-yl}acetamide antimalarial

artérolane N-(2-amino-2-methylpropyl)-2-{cis-dispiro[adamantane- 2,3'-[1,2,4]trioxolane-5',1"-cyclohexan]-4"-yl}acétamide antipaludique

arterolano N-(2-amino-2-metilpropil)-2-{cis-dispiro[adamantano- 2,3'-[1,2,4]trioxolano-5',1"-ciclohexan]-4"-il}acetamida antipalúdico

C22H36N2O4 664338-39-0

O O O H CH3 N O H H2NCH3

137 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

azilsartanum medoxomilum azilsartan medoxomil (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo- 4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-yl]methyl}- 1H-benzimidazol-7-carboxylate angiotensine II receptor antagonist

azilsartan médoxomil 2-éthoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 1,1'-biphényl-4-yl]méthyl}-1H-benzimidazole-7-carboxylate de (5-méthyl-2-oxo-1,3-dioxol-4-yl)méthyle antagoniste du récepteur de l’angiotensine II

azilsartán medoxomilo 2-etoxi-1-{[2'-(5-oxo-4,5-dihidro-1,2,4-oxadiazol-3-il)-1,1'-bifenil- 4-il]metil}-1H-benzoimidazol-7-carboxilato de (5-metil-2-oxo- 1,3-dioxol-4-il)metilo antagonista del receptor de la angiotensina II

C30H24N4O8 863031-24-7

H3C O O O O HN N N

N O

CH3

azoximeri bromidum azoximer bromide poly{[1-(carboxymethyl)piperazin-1-ium-1,4-diyl bromide]ethylene- co-[(piperazin-1,4-diyl 1-oxide)ethylene]} immunomodulator

bromure d'azixomère poly{[bromure de 1-(carboxyméthyl)pipérazin-1-ium- 1,4-diyl]éthylène-co-[(1-oxyde de pipérazine-1,4-diyl)éthylène]} immunomodulateur

bromuro de azoxímero poly{[bromuro de 1-(carboximetil)piperazin-1-io-1,4-diil]etileno- co-[(1-óxido de piperazin-1,4-diil)etileno]} inmunomodulador

[[C8H15BrN2O2]x[C6H12N2O]y]n 892497-01-7

CO2H

N+ N Br x N N O y n

138 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

begacestatum begacestat 5-chloro-N-[(2S)-4,4,4-trifluoro-1-hydroxy-3-(trifluoromethyl)butan- 2-yl]thiophene-2-sulfonamide gamma secretase inhibitor

bégacestat 5-chloro-N-[(2S)-4,4,4-trifluoro-1-hydroxy-3-(trifluorométhyl)butan- 2-yl]thiophène-2-sulfonamide inhibiteur de la secrétase gamma

begacestat 5-cloro-N-[(2S)-4,4,4-trifluoro-1-hidroxi-3-(trifluorometil)butan- 2-il]tiofeno-2-sulfonamida inhibidor de la secretasa gamma

C9H8ClF6NO3S2 769169-27-9

OO H OH

S S CF3 N Cl H CF3

belinostatum belinostat N-hydroxy-3-[3-(N-phenylsulfamoyl)phenyl]prop-2-enamide antitumour agent, inhibitor of histone deacetylase

bélinostat N-hydroxy-3-[3-(phénylsulfamoyl)phényl]prop-2-ènamide agent antitumoral, inhibiteur de la déacétylase de l'histone

belinostat N-hidroxi-3-{3-[(fenilsulfamoil]fenil}prop-2-enamida antitumoral, inhibidor de la desacetilasa de histona

C15H14N2O4S 414864-00-9

O H OH N N S H OO

boceprevirum boceprevir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-dimethylbutanoyl}- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide antiviral

bocéprévir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)]- 3-{(2S)-2-[(tert-butylcarbamoyl)amino]-3,3-diméthylbutanoyl}- 6,6-diméthyl-3-azabicyclo[3.1.0]hexane-2-carboxamide antiviral

boceprevir (1R,2S,5S)-N-[(2Ξ)-4-amino-1-ciclobutil-3,4-dioxobutan-2-il)]- 3-{(2S)-2-[(terc-butilcarbamoil)amino]-3,3-dimetilbutanoil}-6,6-dimetil- 3-azabiciclo[3.1.0]hexano-2-carboxamida antiviral

139 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

C27H45N5O5 394730-60-0

CH3 CH H3C H 3 CH3 CH3 H C CH O 3 3 H O N H H H3C N N N NH2 H H O H O H O

canakinumabum* canakinumab immunoglobulin G1, anti-[Homo sapiens interleukin 1, beta (IL1B)] human monoclonal ACZ885; gamma1 heavy chain (Homo sapiens VH-IGHG1*03) (221-214’)-disulfide with kappa light chain (Homo sapiens V-KAPPA-IGKC*01); (227-227’’:230-230’’)-bisdisulfide dimer immunomodulator

canakinumab immunoglobuline G1, anti-[Homo sapiens interleukine 1, beta (IL1B)] anticorps monoclonal humain ACZ885; chaîne lourde gamma1 (Homo sapiens VH-IGHG1*03) (221-214’)-disulfure avec la chaîne légère kappa (Homo sapiens V-KAPPA-IGKC*01); dimère (227-227’’:230-230’’)-bisdisulfure immunomodulateur

canakinumab inmunoglobulina G1, anticuerpo monoclonal humano ACZ885 anti-[ interleukina 1 de Homo sapiens, beta (IL1B)]; cadena pesada gamma1 (Homo sapiens VH-IGHG1*03) (221-214’)-disulfuro con la cadena ligera kappa (Homo sapiens V-KAPPA-IGKC*01); dímero (227-227’’:230-230’’)-bisdisulfuro inmunomodulador

C6452H9958N1722O2010S42 Light chain 402710-27-4 Heavy chain 402710-25-2

carfilzomibum carfilzomib {(2S)-2-[(morpholin-4-yl)acetamido]-4-phenylbutanoyl}-L-leucyl- N1-{(2S)-1-[(2R)-2-methyloxiran-2-yl]-4-methyl-1-oxopentan-2-yl}- L-phenylalaninamide antineoplastic

carfilzomib {(2S)-2-[(morpholin-4-yl)acétamido]-4-phénylbutanoyl}-L-leucyl- N1-{(2S)-1-[(2R)-2-méthyloxiran-2-yl]-4-méthyl-1-oxopentan-2-yl}- L-phénylalaninamide antinéoplasique

carfilzomib {(2S)-2-[(morfolin-4-il)acetamido]-4-fenilbutanoil}-L-leucil- N1-{(2S)-1-[(2R)-2-metiloxiran-2-il]-4-metil-1-oxopentan-2-il}- L-fenilalaninamida antineoplásico

140 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C40H57N5O7 868540-17-4

O O H O H O H H N N N CH3 N N H H O H O H O CH3 CH3 H3C H3C

ceftarolinum fosamilum ceftaroline fosamil (6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)- 1,2,4-thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)- 1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate antibiotic

céftaroline fosamil (6R,7R)-7-{(2Z)-2-(éthoxyimino)-2-[5-(phosphonoamino)- 1,2,4-thiadiazol-3-yl]acétamido}-3-{[4-(1-méthylpyridin-1-ium-4-yl)- 1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ène- 2-carboxylate antibiotique

ceftarolina fosamilo (6R,7R)-7-{(2Z)-2-(etoxiimino)-2-[5-(fosfonoamino)-1,2,4-tiadiazol- 3-il]acetamido}-3-{[4-(1-metilpiridin-1-io-4-il)-1,3-tiazol-2-il]sulfanil}- 8-oxo-5-tia-1-azabiciclo[4.2.0]oct-2-eno-2-carboxilato antibiótico

C22H21N8O8PS4 229016-73-3

CH3 CO2 O O S N N N + H N CH3 N N S S S H H HO N O HO P NH O

cenersenum cenersen antisense oligonucleotide inhibitor of p53 expression 2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')- 2'-deoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thioguanylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')- P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thioguanylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-2'-deoxycytidine antineoplastic

141 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

cénersen oligonucléotide antisense inhibiteur de l'expression de p53 2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')- 2'-déoxy-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')- P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thioguanylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-2'-déoxycytidine antinéoplasique

cenersén oligonucleótido antisentido inhibidor de la expresión de p53 2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil- (3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil- (3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi-P-tioguanilil- (3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi- P-tiocitidilil-(3'→5')-2'-desoxicitidina antineoplásico

C187H226N62O103P19S19 872847-66-0

cholini fenofibratum choline fenofibrate 2-hydroxy-N,N,N-trimethylethanaminium 2-[4-(4-chlorobenzoyl)= phenoxy]-2-methylpropanoate antihyperlipidaemic

fénofibrate de choline 2-[4-(4-chlorobenzoyl)phénoxy]-2-méthylpropanoate de 2-hydroxy- N,N,N-triméthyléthanaminium antihyperlipidémiant

fenofibrato de colina 2-[4-(4-clorobenzoil)fenoxi]-2-metilpropanoato de 2-hidroxi- N,N,N-trimetiletanaminio antihiperlipémico

+ - C5H14NO .C17H14ClO4 856676-23-8

- Cl O CO2 H3C CH3 + N H3CCH3 HO CH3 O

142 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

cinaciguatum cinaciguat 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)phenyl]methoxy}phenyl)= ethyl]amino}methyl)benzoic acid guanylate cyclase activator

cinaciguat acide 4-({(4-carboxybutyl)[2-(2-{[4-(2-phényléthyl)phényl]méthoxy}= phényl)éthyl]amino}méthyl)benzoïque activateur de la guanylate cyclase

cinaciguat ácido 4-({(4-carboxibutil)[2-(2-{[4-(2-feniletil)fenil]metoxi}fenil)= etil]amino}metil)benzoico activador de la guanilato ciclasa

C36H39NO5 329773-35-5

CO2H

O N CO2H

contusugenum ladenovecum* contusugene ladenovec (Recombinant) replication restricted adenovirus (type 5) vector, E1 deleted, partial E3 deletion, containing/expressing a wild type p53 gene driven by a cytomegalovirus promoter induce cell growth arrest and apotopsis

contusugène ladénovec Vecteur adénovirus (type 5) recombinant défectif, délété de E1 et partiellement de E3, contenant le gène p53 sauvage sous le contrôle du promoteur cytomégalovirus induit l'arrêt de la croissance cellulaire et l'apoptose

contusugén ladenovec Vector adenovirus (tipo 5) recombinante defectivo, con deleción de E1 y parcialmente de E3, que contiene el gen p53 salvaje controlado por el promotor de cytomegalovirus induce la detención del crecimiento celular y la apoptosis

600735-73-7

dapagliflozinum dapagliflozin (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}- D-glucitol antidiabetic

dapagliflozine (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-éhoxyphényl)méthyl]phényl}- D-glucitol antidiabétique

dapagliflozina (1S)-1,5-anhidro-1-C-{4-cloro-3-[(4-etoxifenil)metil]fenil}-D-glucitol hipoglucemiante

143 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

C21H25ClO6 461432-26-8

O CH3

O OH HO OH

delimotecanum delimotecan poly{[2-O-(carboxymethyl)-α-D-glucopyranosyl-(1→6)]-co-[2-O-(15- {[(4S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro- 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl]oxy}-2,5,8,11- tetraoxo-3,6,9,12-tetraazapentadecyl)-α-D-glucopyranosyl- (1→6)]-co-[α-D-glucopyranosyl-(1→6)]} antineoplastic

délimotécan poly{[2-O-(carboxyméthyl)-α-D-glucopyranosyl-(1→6)]-co-[2-O-(15- {[(4S)-4,11-diéthyl-4-hydroxy-3,14-dioxo-3,4,12,14-tétrahydro- 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléin-9-yl]oxy}-2,5,8,11- tétraoxo-3,6,9,12-tétraazapentadécyl)-α-D-glucopyranosyl-(1→6)]- co-[α-D-glucopyranosyl-(1→6)]} antinéoplasique

delimotecán poli{[2-O-(carboximetil)-α-D-glucopiranosil-(1→6)]-co-[2-O-(15-{[(4S)- 4,11-dietil-4-hidroxi-3,14-dioxo-3,4,12,14-tetrahidro- 1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin-9-il]oxi}-2,5,8,11- tetraoxo-3,6,9,12-tetraazapentadecil)-α-D-glucopiranosil-(1→6)]- co-[α-D-glucopiranosil-(1→6)]} antineoplásico

144 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

[C39H46N6O14[C6H10O5]x[C8H12O7]y]n 187852-63-7 (for Na salt)

HO O OH HO O OH O x CH O 3 O OH OH O HO O N HO2C O y O N OH H3C HO O H O O H H O N N N N O H H O O n

dovitinibum dovitinib 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazole- 2-yl]quinolin-2(1H)-one antineoplastic

dovitinib 4-amino-5-fluoro-3-[6-(4-méthylpipérazin-1-yl)-1H-benzimidazol- 2-yl]quinoléin-2(1H)-one antinéoplasique

dovitinib 4-amino-5-fluoro-3-[6-(4-metilpiperazin-1-il)-1H-benzoimidazol- 2-il]quinolin-2(1H)-ona antineoplásico

C21H21FN6O 405169-16-6

O N N N CH3

HN N H

NH2

eldecalcitolum eldecalcitol (5Z,7E)-2β-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene- 1α,3β,25-triol vitamin D analogue

eldécalcitol (5Z,7E)-2β-(3-hydroxypropoxy)-9,10-sécocholesta-5,7,10(19)-triène- 1α,3β,25-triol analogue de la vitamine D

eldecalcitol (5Z,7E)-2β-(3-hidroxipropoxi)-9,10-secocolesta-5,7,10(19)-trieno- 1α,3β,25-triol análogo de la vitamina D

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C30H50O5 104121-92-8

H H3C CH 3 CH3 H CH3 HO

CH2

HO OH H H HO OH

elvitegravirum elvitegravir 6-[(3-chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy-3-methylbutan- 2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid antiviral

elvitégravir acide 6-[(3-chloro-2-fluorophényl)méthyl]-1-[(2S)-1-hydroxy- 3-méthylbutan-2-yl]-7-méthoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylique antiviral

elvitegravir ácido 6-[(3-cloro-2-fluorofenil)metil]-1-[(2S)-1-hidroxi-3-metilbutan- 2-il]-7-metoxi-4-oxo-1,4-dihidroquinolina-3-carboxílico antiviral

C23H23ClFNO5 697761-98-1

CH3 HO

CH3 H CH3 O N

Cl CO2H F O

epetirimodum epetirimod 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine immunomodulator

épétirimod 1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridin-4-amine immunomodulateur

epetirimod 1-(2-metilpropil)-1H-imidazo[4,5-c][1,5]naftiridin-4-amina inmunomodulador

146 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C13H15N5 227318-71-0

H3C

H3C N N N

N NH2

epoetinum kappa epoetin kappa 1-165-erythropoietin (human JR-013), glycoform κ antianaemic

époétine kappa érythropoïétine (humaine JR-013)-(1-165), glycoforme κ antianémique

epoetina kappa 1-165-eritropoyetina (humana JR-013), glicoforma κ antianémico

C809H1301N229O240S5 879555-13-2

eribulinum eribulin (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hydroxypropyl]-3-methoxy- 26-methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28- triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]= pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one antineoplastic

éribuline (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hydroxypropyl]-3-méthoxy- 26-méthyl-20,27-diméthylidènehexacosahydro-11,15:18,21:24,28- triépoxy-7,9-éthano-12,15-méthano-9H,15H-furo[3,2-i]furo[2',3':5,6]= pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one antinéoplasique

eribulina (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24 S,26R,28R,29aS)-2-[(2S)-3-amino-2-hidroxipropil]-26-metil- 20,27-dimetilideno-3-metoxihexacosahidro-11,15:18,21:24,28- triepoxi-7,9-etano-12,15-metano-9H,15H-furo[3,2-i]furo[2',3':5,6]= pirano[4,3-b][1,4]dioxaciclopentacosin-5(4H)-ona antineoplásico

C40H59NO11 253128-41-5

H3C O H H H H N H 2 O H H H O HO H H O O CH2 O H H H H O O H H CH3 O O H H H

H2C

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faxeladolum faxeladol 3-[(1R,2R)-2-(dimethylaminomethyl)cyclohexyl]phenol analgesic

faxéladol 3-{(1R,2R)-2-[(diméthylamino)méthyl]cyclohexyl}phenol analgésique

faxeladol 3-[(1R,2R)-2-(dimetilaminometil)ciclohexil]fenol analgésico

C15H23NO 433265-65-7

CH3 N CH3 H H

ferricum carboxymaltosum ferric carboxymaltose poly[D-glucopyranosyl(1→4)]-D-gluconic acid complex of hydrated iron(III) oxide haematinic

carboxymaltose ferrique complexe d'oxide de fer(III) et d'acide poly[D-glucopyranosyl(1→4)]- D-gluconique hydraté hématinique

carboximaltosa férrica ácido poli[D-glucopiranosil(1→4)]-D-glucónico complejo de óxido de hierro(III) hidratado hematínico

FeIIIw([C6H10O5]aC6H11O7)x(OH)yOz.nH2O 9007-72-1

flovagatranum flovagatran (1R)-1-{N-[(benzyloxy)carbonyl]-D-phenylalanyl-L-prolinamido}= butylboronic acid thrombin inhibitor

flovagatran acide (1R)-1-{N-[(benzyloxy)carbonyl]-D-phénylalanyl-L-prolinamido} butylboronique inhibiteur de la thrombine

flovagatrán ácido (1R)-1-{N-[(benciloxi)carbonil]-D-fenilalanil-L-prolinamido}= butilborónico inhibidor de la trombina

148 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C27H36BN3O7 871576-03-3

CH3 O O O H H H OH O N N B N H O H OH

gantenerumabum* gantenerumab immunoglobulin G1, anti-(human beta-amyloid peptides Aβ42 and Aβ40) human monoclonal antibody; gamma1 heavy chain (Homo sapiens VH-IGHG1) (229-215’)-disulfide with kappa light chain (Homo sapiens V-KAPPA-IGKC); (235-235”:238-238”)-bisdisulfide ٛ oured immunomodulator

ganténérumab immunoglobuline G1, anti-(peptides beta-amyloides Aβ42 et Aβ40 humains) anticorps monoclonal humain; chaîne lourde gamma1 (Homo sapiens VH-IGHG1) (229-215’)-disulfure avec la chaîne légère kappa (Homo sapiens V-KAPPA-IGKC); dimère (235-235”:238-238”)-bisdisulfure immunomodulateur

gantenerumab inmunoglobulina G1, anticuerpo monoclonal humano anti-(péptidos beta-amiloides Aβ42 et Aβ40 humanos); cadena pesada gamma1 (Homo sapiens VH-IGHG1) (229-215’)-disulfuro con la cadena ligera kappa (Homo sapiens V-KAPPA-IGKC); dimero (235-235”:238- 238”)-bisdisulfuro inmunomodulador

89957-37-9 γ1- heavy chain / Chaîne lourde γ1 / Cadena pesada γ1

QVELVESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA 50 INASGTRTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARGK 100 GNTHKPYGYV RYFDVWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA 150 LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS 200 SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF 250 LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP 300 REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG 350 QPREPQVYTL PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY 400 KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL 450 SLSPGK 456

κ-light chain / Chaîne légère κ / Cadena ligera κ

DIVLTQSPAT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY 50 GASSRATGVP ARFSGSGSGT DFTLTISSLE PEDFATYYCL QIYNMPITFG 100 QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150 VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200 GLSSPVTKSF NRGEC 215

The position of cysteine (C) residues that form disulphide bridges and asparagine residues that are N-glycosylated are in bold.

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golotimodum golotimod D-γ-glutamyl-L-tryptophan immonomudulator

golotimod D-γ-glutamyl-L-tryptophane immunomodulateur

golotimod D-γ-glutamil-L-triptófano inmunomodulador

C16H19N3O5 229305-39-9

H NH 2 H NCO2H HO2C O H

N H

ibalizumabum* ibalizumab immunoglobulin G4, anti-(human CD4) humanized monoclonal antibody Hu5A8 (TNX-355); gamma4 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR [8.8.15] from clone Mu5A8)- Homo sapiens IGHG4*01] (136-219’)-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR [12.3.8] from clone Mu5A8)-Homo sapiens IGKC*01] ; (228- 228’:231-231”)-bisdisulfide dimer antiviral

ibalizumab immunoglobuline G4, anti-(CD4 humain) anticorps monoclonal humanisé Hu5A8 (TNX-355); chaîne lourde gamma4 [VH humanisé (Homo sapiens FR/Mus musculus CDR [8.8.15] du clone 5A8)-Homo sapiens IGHG4] (136-219’)-disulfure avec la chaîne légère kappa [V- KAPPA humanisé (Homo sapiens FR/Mus musculus CDR [12.3.8] du clone Mu5A8)-Homo sapiens IGKC*01]; dimère (228-228”:231- 231”)-bisdisulfure antiviral

ibalizumab inmunoglobulina G4, anti-(CD4 humano) anticuerpo monoclonal humanizado Hu5A8 (TNX-355); cadena pesada gamma4 [VH humanizado (Homo sapiens FR/Mus musculus CDR [8.8.15] del clon 5A8)-Homo sapiens IGHG4] (136-219’)-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR [12.3.8] del clon Mu5A8)-Homo sapiens IGKC*01]; dímero (228-228”:231-231”)-bisdisulfuro antiviral

150 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

680188-33-4

Ig γ4-heavy chain / Chaîne lourde Ig γ4 / Cadena pesada Ig γ4 QVQLQQSGPE VVKPGASVKM SCKASGYTFT SYVIHWVRQK PGQGLDWIGY 50 INPYNDGTDY DEKFKGKATL TSDTSTSTAY MELSSLRSED TAVYYCAREK 100 DNYATGAWFA YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL 150 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200 KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV 350 YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 449

Ig κ-light chain / Chaîne légère Ig κ / Cadena ligera Ig κ

DIVMTQSPDS LAVSLGERVT MNCKSSQSLL YSTNQKNYLA WYQQKPGQSP 50 KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSVQAEDVA VYYCQQYYSY 100 RTFGGGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219

idrabiotaparinuxum natricum idrabiotaparinux sodium nonasodium methyl (2-deoxy-3,4-di-O-methyl-2-{6-[5-(2- oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido]= hexanamido}-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-(2,3-di-O-methyl- β-D-glucopyranosyluronate)-(1→4)-(2,3,6-tri-O-sulfo- α-D-glucopyranoside)-(1→4)-(2,3-di-O-methyl- α-L-idopyranosyluronate)-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopyranoside antithrombotic

idrabiotaparinux sodique 2-déoxy-3,4-di-O-méthyl-2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahydro- 1H-thiéno[3,4-d]imidazol-4-yl]pentanoyl}amino)hexanoyl]amino}- 6-O-sulfo-α-D-glucopyranosyl-(1→4)-2,3-di-O-méthyl- β-D-glucopyranuronosyl-(1→4)-2,3,6-tri-O-sulfo-α-D-glucopyranosyl- (1→4)-2,3-di-O-méthyl-α-L-idopyranuronosyl-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopyranoside de méthyle nonasodique antithrombotique

idrabiotaparinux sódico 2-desoxy-3,4-di-O-metil-2-{[6-({5-[(3aS,4S,6aR)-2-oxohexahidro- 1H-tieno[3,4-d]imidazol-4-il]pentanoil}amino)hexanoil]amino}- 6-O-sulfo-α-D-glucopiranosil-(1→4)-2,3-di-O-metil- β-D-glucopiranuronosil-(1→4)-2,3,6-tri-O-sulfo-α-D-glucopiranosil- (1→4)-2,3-di-O-metil-α-L-idopiranuronosil-(1→4)-2,3,6-tri-O-sulfo- α-D-glucopiranosido de metilo y nonasodico antitrombótico

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C53H79N4Na9O51S8 405159-59-3

O SO3Na O O NaO3S SO3Na O O O O O NaO3S O CO Na CH3 SO Na CO Na O 2 O 3 2 OCH 3 SO3Na O O O O OCH OCH O 3 3 OCH SO3Na 3 H3CO O S HN O OCH3 H H H N O NH H HN O

laropiprantum laropiprant [(3R)-4-[(4-chlorophenyl)methyl]-7-fluoro-5-(methanesulfonyl)- 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid prostanoid DP1 receptor antagonist

laropiprant acide [(3R)-4-[(4-chlorophényl)méthyl]-7-fluoro-5-(méthanesulfonyl)- 1,2,3,4-tétrahydrocyclopenta[b]indol-3-yl]acétique antagoniste du récepteur DP1 des prostanoïdes

laropiprant ácido [(3R)-4-[(4-clorofenil)metil]-7-fluoro-5-(metanosulfonil)- 1,2,3,4-tetrahidrociclopenta[b]indol-3-il]acético antagonista del receptor DP1 de prostanoides

C21H19ClFNO4S 571170-77-9

F CO2H

N H

O S CH3 Cl O

levamlodipinum levamlodipine 3-ethyl 5-methyl (4S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)- 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate calcium channel blocker

lévamlodipine (4S)-2-[(2-aminoéthoxy)méthyl]-4-(2-chlorophényl)-6-méthyl- 1,4-dihydropyridine-3,5-dicarboxylate de 3-éthyle et de 5-méthyle antagoniste des canaux calciques

levamlodipino (4S)-2-[(2-aminoetoxi)metil]-4-(2-clorofenil)-6-metil- 1,4-dihidropiridina-3,5-dicarboxilato de 3-etilo y 5-metilo antagonista de los canales del calcio

152 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C20H25ClN2O5 103129-82-4

H H3C N NH2 O

O O CH3 H3C H O O Cl

lonaprisanum lonaprisan 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor- 17α-pregna-5,9-dien-3-one progesterone receptor antagonist

lonaprisan 11β-(4-acétylphényl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor- 17α-prégna-5,9-dién-3-one antagoniste des récepteurs de la progestérone

lonaprisán 11β-(4-acetilfenil)-20,20,21,21,21-pentafluoro-17-hidroxi-19-nor- 17α-pregna-5,9-dien-3-ona antagonista de los receptores de progesterona

C28H29F5O3 211254-73-8

H C 3 OH CF H CH3 3 F H F

H O

metenkefalinum metenkefalin L-tyrosylglycylglycyl-L-phenylalanyl-L-methionine β-endorphin human-(1-5)-peptide µ and δ opioid receptors agonist

métenkefaline L-tyrosylglycylglycyl-L-phénylalanyl-L-méthionine β-endorphine humaine-(1-5)-peptide agoniste des récepteurs opioïdes µ et δ

metencefalina L-tirosilglicilglicil-L-fenilalanil-L-metionina β-endorfina humana-(1-5)-peptido agonista de los receptores µ y δ de opiáceos

C27H35N5O7S 58569-55-4

H L-Tyr Gly Gly L-Phe L-Met OH

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milveterolum milveterol N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy- 2-phenylethyl]amino}phenyl)ethyl]amino}ethyl]phenyl}formamide bronchodilator

milvétérol N-{2-hydroxy-5-[(1R)-1-hydroxy-2-{[2-(4-{[(2R)-2-hydroxy- 2-phényléthyl]amino}phényl)éthyl]amino}éthyl]phényl}formamide bronchodilatateur

milveterol N-{2-hidroxi-5-[(1R)-1-hidroxi-2-{[2-(4-{[(2R)-2-hidroxi- 2-feniletil]amino}fenil)etil]amino}etil]fenil}formamida broncodilatador

C25H29N3O4 652990-07-3

H OH H N

HO N H HN H HOH

motesanibum motesanib N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-{[(pyridin-4-yl)methyl]= amino}pyridine-3-carboxamide antineoplastic

motésanib N-(3,3-diméthyl-2,3-dihydro-1H-indol-6-yl)-2-{[(pyridin-4-yl)méthyl]= amino}pyridine-3-carboxamide antinéoplasique

motesanib N-(3,3-dimetil-2,3-dihidro-1H-indol-6-il)-2-{[(piridin-4-il)metil]= amino}piridina-3-carboxamida antineoplásico

C22H23N5O 453562-69-1

HN CH3

NH O CH3 N N N H

nepiderminum nepidermin human epidermal growth factor, recombinant DNA origin epidermal growth factor

népidermine facteur humain de croissance épidermique, origine ADN recombinant facteur de croissance épidermique

nepidermina factor de crecimiento epidérmico humano; origen: ADN recombinante factor de crecimiento epidérmico

154 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C270H401N73O83S7 62253-63-8

HAsn Ser Asp Ser Glu Cys Pro Leu Ser His Asp Gly Tyr Cys 10 Leu His Asp Gly Val Cys Met Tyr Ile Glu Ala Leu Asp Lys 20 Tyr Ala Cys Asn Cys Val Val Gly Tyr Ile Gly Glu Arg Cys 30 40 Gln Tyr Arg Asp Leu Lys Trp Trp Glu Leu Arg OH 50

neratinibum neratinib (2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano- 7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide antineoplastic

nératinib (2E)-N-[4-({3-chloro-4-[(pyridin-2-yl)méthoxy]phényl}amino)-3-cyano- 7-éthoxyquinoléin-6-yl]-4-(diméthylamino)but-2-énamide antinéoplasique

neratinib (2E)-N-[4-({3-cloro-4-[(piridin-2-yi)metoxi]fenil}amino)-3-ciano- 7-etoxiquinolin-6-il]-4-(dimetilamino)but-2-enamida antineoplásico

C30H29ClN6O3 698387-09-6

H3C O N

CH3 HN CN N HN Cl H3C O

O N

perampanelum perampanel 2-(6'-oxo-1'-phenyl-1',6'-dihydro[2,3'-bipyridin]-5'-yl)benzonitrile AMPA receptor antagonist

pérampanel 2-(6'-oxo-1'-phenyl-1',6'-dihydro[2,3'-bipyridin]-5'-yl)benzonitrile antagoniste des récepteurs de l'AMPA

perampanel 2-(1'-fenil-6'-oxo-1',6'-dihidro[2,3'-bipiridin]-5'-il)benzonitrilo antagonista de los receptores del AMPA

C23H15N3O 380917-97-5

N CN

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peretinoinum peretinoin (2E,4E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,4,6,10,14- pentaenoic acid retinoid derivative, antineoplastic

pérétinoin acide (2E,4E,6E,10E)-3,7,11,15-tétraméthylhexadéca-2,4,6,10,14- penténoïque rétinoïde, antinéoplasique

peretinoína ácido (2E,4E,6E,10E)-3,7,11,15-tetrametilhexadeca-2,4,6,10,14- pentaenoico retinoide, antineoplásico

C20H30O2 81485-25-8

CH3 CH3 CH3 CH3

CO2H H3C

pexacerfontum pexacerfont N-[(2R)-butan-2-yl]-8-(6-methoxy-2-methylpyridin-3-yl)- 2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-4-amine antidepressant

pexacerfont N-[(2R)-butan-2-yl]-8-(6-méthoxy-2-méthylpyridin-3-yl)- 2,7-diméthylpyrazolo[1,5-a][1,3,5]triazin-4-amine antidépresseur

pexacerfont N-[(2R)-butan-2-il]-8-(6-metoxi-2-metilpiridin-3-il)- 2,7-dimetilpirazolo[1,5-a][1,3,5]triazin-4-amina antidepresivo

C18H24N6O 459856-18-9

CH H C H N 3 3 N N H C 3 H N N H3C N OCH3 H3C

pimavanserinum pimavanserin 1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)- 3-{[4-(2-methylpropoxy)phenyl]methyl}urea serotonin receptor antagonist

pimavansérine 1-[(4-fluorophényl)méthyl]-1-(1-méthylpipéridin-4-yl)- 3-{[4-(2-méthylpropoxy)phényl]méthyl}urée antagoniste des récepteurs de la sérotonine

pimavanserina 1-[(4-fluorofenil)metil]-1-(1-metilpiperidin-4-il)- 3-{[4-(2-metilpropoxi)fenil]metil}urea antagonista del receptor de la serotonina

156 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C25H34FN3O2 706779-91-1

CH3 N CH3 F O CH3 H N N

piragliatinum piragliatin (2R)-2-[3-chloro-4-(methanesulfonyl)phenyl]- 3-[(1R)-3-oxocyclopentyl]-N-(pyrazin-2-yl)propanamide antidiabetic

piragliatine (2R)-2-[3-chloro-4-(méthanesulfonyl)phényl]- 3-[(1R)-3-oxocyclopentyl]-N-(pyrazin-2-yl)propanamide antidiabétique

piragliatina (2R)-2-[3-cloro-4-(metanosulfonil)fenil]-3-[(1R)-3-oxociclopentil]- N-(pirazin-2-il)propanamida hipoglucemiante

C19H20ClN3O4S 625114-41-2

OO S N H3C O

Cl N N H H H O

pomalidomidum pomalidomide 4-amino-2-[(3RS)-2,6-dioxopiperidin-3-yl]-2H-isoindole-1,3-dione antineoplastic

pomalidomide 4-amino-2-[(3RS)-2,6-dioxopipéridin-3-yl]-2H-isoindole-1,3-dione antinéoplasique

pomalidomida 4-amino-2-[(3RS)-2,6-dioxopiperidin-3-il]-2H-isoindol-1,3-diona antineoplásico

C13H11N3O4 19171-19-8

O O and enantiomer N NH et énantiomère H y enantiómero O O NH2

157 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

posaraprostum posaraprost propan-2-yl (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hydroxy-5-phenylpent- 1-en-1-yl]-5-oxocyclopent-3-en-1-yl}hept-5-enoate anti-inflammatory

posaraprost (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hydroxy-5-phénylpent-1-én-1-yl]- 5-oxocyclopent-3-én-1-yl}hept-5-énoate de propan-2-yle anti-inflammatoire

posaraprost (5Z)-7-{(1R,2S)-2-[(1E,3S)-3-hidroxi-5-fenilpent-1-en-1-il]- 5-oxociclopent-3-en-1-ilo}-hept-5-enoato de propan-2-ilo antiinflamatorio

C26H34O4 172740-14-6

O H O CH3

O CH3 H HOH

pyronaridinum pyronaridine 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]- 2,6-bis[(pyrrolidin-1-yl)methyl]phenol antimalarial

pyronaridine 4-[(7-chloro-2-méthoxybenzo[b][1,5]naphthyridin-10-yl)amino]- 2,6-bis[(pyrrolidin-1-yl)méthyl]phénol antipaludique

pironaridina 4-[(7-cloro-2-metoxibenzo[b][1,5]naftiridin-10-il)amino]- 2,6-bis[(pirrolidin-1-il)metil]fenol antipalúdico

C29H32ClN5O2 74847-35-1

N Cl

H3CO N HN N

158 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

rabeximod rabeximod 2-(9-chloro-2,3-dimethyl-6H-indolo[2,3-b]quinoxalin-6-yl)- N-[2-(dimethylamino)ethyl]acetamide immunomodulator

rabeximod 2-(9-chloro-2,3-diméthyl-6H-indolo[2,3-b]quinoxalin-6-yl)- N-[2-(diméthylamino)éthyl]acétamide immunomodulateur

rabeximod 2-(9-cloro-2,3-dimetil-6H-indolo[2,3-b]quinoxalin-6-il)- N-[2-(dimetilamino)etil]acetamida inmunomodulador

C22H24ClN5O 872178-65-9

CH3 Cl N

CH3 N N H N CH3 N

O CH3

raltegravirum raltegravir N-[(4-fluorophenyl)methyl]-5-hydroxy-1-methyl-2-[2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl]-6-oxo- 1,6-dihydropyrimidine-4-carboxamide antiviral

raltégravir N-[(4-fluorophényl)méthyl]-5-hydroxy-1-méthyl-2-[2-(5-méthyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl]-6-oxo- 1,6-dihydropyrimidine-4-carboxamide antiviral

raltegravir N-[(4-fluorofenil)metil]-5-hidroxi-1-metil-2-[2-(5-metil-1,3,4-oxadiazol- 2-carboxamido)propan-2-il]-6-oxo-1,6-dihidropirimidina- 4-carboxamida antiviral

C20H21FN6O5 518048-05-0

O O H3C CH3 O N N N H3C H H N N N H3C OH F O

regrelorum regrelor N6-(N-ethylcarbamoyl)-2',3'-O-[(1S,2E)-3-phenylprop-2-ene-1,1-diyl]- 5'-adenylic acid platelet aggregation inhibitor

159 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

régrélor acide N6-(N-éthylcarbamoyl)-2',3'-O-[(1S,2E)-3-phénylprop-2-ène- 1,1-diyl]-5'-adénylique antiagrégant plaquettaire

regrelor ácido N6-(N-etilcarbamoil)-2',3'-O-[(1S,2E)-3-fenilprop-2-eno- 1,1-diilo]-5'-adenílico inhibidor de la agregacion plaqueteria

C22H25N6O8P 787548-03-2

H3C N NH H N N

O O N N P O HO OH

O O

rolapitantum rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)- 8-phenyl-1,7-diazaspiro[4.5]decan-2-one neurokinin NK1 receptor antagonist

rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluorométhyl)phényl]éthoxy}méthyl)- 8-phényl-1,7-diazaspiro[4.5]décan-2-one antagoniste du récepteur NK1 de la neurokinine

rolapitant (5S,8S)-8-({(1R)-1-[3,5-bis(trifluorometil)fenil]etoxi}metil)-8-fenil- 1,7-diazaspiro[4.5]decan-2-ona antagonista del receptor NK1 de neurokinina

C25H26F6N2O2 552292-08-7

HN CF3

NH O CF3 HCH3

160 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

romiplostimum* romiplostim L-methionyl[human immunogloblin heavy constant gamma 1-(227 C-terminal residues)-peptide (Fc fragment)] fusion protein with 41 amino acids peptide, (7-7':10,10')-bisdisulfide dimer platelet stimulating factor (through Mpl receptor)

romiplostim (7-7':10,10')-bisdisulfure du dimère de la protéine de fusion entre le L-méthionyl[chaine constante gamma 1 de l’immunoglobuline humaine-(227 aminoacides C-terminaux)-peptide (fragment Fc)] et un peptide de 41 aminoacides facteur de stimulation plaquettaire (par le récepteur MpI)

romiplostim (7-7':10,10')-bisdisulfuro del dímero de la proteína de fusión entre la L-metionil[cadena constante gamma 1 de la inmunoglobulina humana-(227 aminoácidos C-terminales)-péptido (fragmento Fc)] y un péptido de 41 aminoácidos factor estimulante de plaquetas (mediante el receptor Mpl)

C2634H4086N722O790S18 267639-76-9

Monomer / Monomère / Monómero MDKTHTCPPC PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE 50 DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY 100 KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT KNQVSLTCLV 150 KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ 200 GNVFSCSVMH EALHNHYTQK SLSLSPGKGG GGGIEGPTLR QWLAARAGGG 250 GGGGGIEGPT LRQWLAARA 269

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 7-7' 10-10' 42-102 42'-102' 148-206 148'-206'

ronacaleretum ronacaleret 3-{3-[(2R)-3-{[1-(2,3-dihydro-1H-inden-2-yl)-2-methylpropan- 2-yl]amino}-2-hydroxypropoxy]-4,5-difluorophenyl}propanoic acid antagonist of the G-protein coupled calcium sensing receptor

ronacaléret acide 3-{3-[(2R)-3-{[1-(2,3-dihydro-1H-indèn-2-yl)-2-méthylpropan- 2-yl]amino}-2-hydroxypropoxy]-4,5-difluorophényl}propanoïque antagoniste du récepteur sensible au calcium couplé à la protéine G

ronacaleret ácido3-{3-[(2R)-3-{[1-(2,3-dihidro-1H-inden-2-il)-2-metilpropan- 2-il]amino}-2-hidroxipropoxi]-4,5-difluorofenil}propanoico antagonista del receptor sensible al calcio acoplado a proteína G

C25H31F2NO4 753449-67-1

F F H3C CH3

N O CO2H H HOH

161 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

ropidoxuridinum ropidoxuridine 1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one antineoplastic

ropidoxuridine 1-(2-déoxy-β-D-érythro-pentofuranosyl)-5-iodopyrimidin-2(1H)-one antinéoplasique

ropidoxuridina 1-(2-desoxi-β-D-eritro-pentofuranosil)-5-iodopirimidin-2(1H)-ona antineoplásico

C9H11IN2O4 093265-81-7

I N

HO O N O

rosonabantum rosonabant (5RS)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)- 4,5-dihydro-1H-pyrazole-3-carboxamide cannabinoid receptor antagonist

rosonabant (5RS)-5-(4-chlorophényl)-1-(2,4-dichlorophényl)-N-(pipéridin-1-yl)- 4,5-dihydro-1H-pyrazole-3-carboxamide antagoniste des récepteurs cannabinoïdes

rosonabant (5RS)-5-(4-clorofenil)-1-(2,4-diclorofenil)-N-(piperidin-1-il)- 4,5-dihidro-1H-pirazol-3-carboxamida antagonista del receptor de cannabinoides

C21H21Cl3N4O 861151-12-4

Cl O N N N N H and enantiomer Cl et énantiomère H y enantiómero

salirasibum salirasib 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]sulfanyl}benzoic acid antineoplastic

salirasib acide 2-{[(2E,6E)-3,7,11-triméthyldodéca-2,6,10-trién-1-yl]sulfanyl}= benzoïque antinéoplasique

salirasib ácido 2-{[(2E,6E)-3,7,11-trimetildodeca-2,6,10-trien-1-il]sulfanil}= benzoico antineoplásico

162 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C22H30O2S 162520-00-5

CO2H CH3 CH3 CH3

S CH3

sitimagenum ceradenovecum* sitimagene ceradenovec (recombinant) replication restricted adenovirus (type 5) vector, E1 and E3 deleted, containing/expressing the Herpes simplex virus thymidine kinase (HSV-tk) gene antineoplastic

sitimagène céradénovec Vecteur adénovirus (type 5 recombinant défectif, délété de E1 et E3, contenant le gène thymidine kinase du virus de l’herpès simplex (Herpes simplex virus - HSV-tk) antinéoplasique

sitimagén ceradenovec Vector adenovirus (tipo 5 recombinante defectivo,con deleción de E1 y E3, que contiene el gen timidina kinasa del virus del herpes simplex (Herpes simplex virus - HSV-tk) antineoplásico

898830-54-1

sotrastaurinum sotrastaurin 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]- 1H-pyrrole-2,5-dione protein kinase C inhibitor

sotrastaurine 3-(1H-indol-3-yl)-4-[2-(4-méthylpipérazin-1-yl)quinazolin-4-yl]- 1H-pyrrole-2,5-dione inhibiteur de la protéine kinase C

sotrastaurina 3-(1H-indol-3-il)-4-[2-(4-metilpiperazin-1-il)quinazolin-4-il]-1H-pirrol- 2,5-diona inhibidor de la proteinquinasa C

C25H22N6O2 425637-18-9

H O N O

N N N H N

N CH3

163 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

taranabantum taranabant N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl}- 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide cannabinoid receptor antagonist

taranabant N-[(2S,3S)-4-(4-chlorophényl)-3-(3-cyanophényl)butan-2-yl}- 2-méthyl-2-{[5-(trifluorométhyl)pyridin-2-yl]oxy}propanamide antagoniste des récepteurs cannabinoïdes

taranabant N-[(2S,3S)-4-(4-clorofenil)-3-(3-cianofenil)butan-2-il}-2-metil- 2-{[5-(trifluorometil)piridin-2-il]oxi}propanamida antagonista de los receptores de cannabinoides

C27H25ClF3N3O2 701977-09-5

O 3C HH O CF3 NC N H H H3CCH3 N

tarenflurbilum tarenflurbil (2R)-2-(2-fluoro-[1,1'-biphenyl-4-yl])propanoic acid apoptosis regulator

tarenflurbil (2R)-2-(2-fluoro-[1,1'-biphényl-4-yl])propanoic acid régulateur de l'apoptose

tarenflurbilo ácido (2R)-2-(2-fluoro-[1,1'-bifenil-4-il])propanoico regulador de la apoptosis

C15H13FO2 051543-40-9

H CH3 F CO2H

teplizumabum* teplizumab immunoglobulin G1, anti-[human CD3 epsilon (CD3E)] humanized monoclonal antibody MGA031 [hOKT3gamma1(Ala-Ala)]; gamma1 heavy chain 236L>A, 337L>A [humanized VH (Homo sapiens FR/Mus musculus CDR from clone OKT3)-Homo sapiens IGHG1*01, 117L>A (CH2 1.3), 118L>A (CH2 1.2)] (222-213’)-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR from clone OKT3)-Homo sapiens IGKC*01] ; (228- 228”: 231-231”)-bisdisulfide dimer immunomodulator

164 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

téplizumab immunoglobuline G1, anti-[CD3 epsilon humain (CD3E)] anticorps monoclonal humanisé MGA031 [hOKT3gamma1(Ala-Ala)]; chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR du clone OKT3)-Homo sapiens IGHG1*01, 117L >A (CH2 1.3), 118L>A (CH2 1.2)] (222-213’)-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR du clone OKT3)-Homo sapiens IGKC*01]; dimère (228-228”: 231-231”)- bisdisulfure immunomodulateur

teplizumab inmunoglobulina G1, anti-[CD3 epsilon humano (CD3E)] anticuerpo monoclonal humanizado MGA031 [hOKT3gamma1(Ala-Ala)]; cadena pesada gamma1 [VH humanizada (Homo sapiens FR/Mus musculus CDR del clon OKT3)-Homo sapiens IGHG1*01, 117L >A (CH2 1.3) , 118L>A (CH2 1.2)] (222-213’)-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR del clon OKT3)-Homo sapiens IGKC*01]; dímero (228-228”: 231-231”)-bisdisulfuro inmunomodulador

C6462H9938N1738O2022S46 876387-05-2

Heavy chain / Chaîne lourde / Cadena pesada QVQLVQSGGG VVQPGRSLRL SCKASGYTFT RYTMHWVRQA PGKGLEWIGY 50 INPSRGYTNY NQKVKDRFTI SRDNSKNTAF LQMDSLRPED TGVYFCARYY 100 DDHYCLDYWG QGTPVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPEAAGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCSASSSVS YMNWYQQTPG KAPKRWIYDT 50' SKLASGVPSR FSGSGSGTDY TFTISSLQPE DIATYYCQQW SSNPFTFGQG 100' TKLQITRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150' NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200' SSPVTKSFNR GEC 213' Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 23'-87' 23'''-87''' 133'-193' 133'''-193''' 146-202 146''-202'' 213'-222 213'''-222'' 228-228'' 231-231'' 263-323 263''-323'' 369-427 369''-427''

terameprocolum terameprocol 1,1'-[(2R,3S)-2,3-dimethylbutane-1,4-diyl]bis(3,4-dimethoxybenzene) antineoplastic

térameprocol 1,1'-[(2R,3S)-2,3-diméthylbutane-1,4-diyl]bis(3,4-diméthoxybenzène) antinéoplasique

terameprocol 1,1'-[(2R,3S)-2,3-dimetilbutano-1,4-diil]bis(3,4-dimetoxibenceno) antineoplásico

C22H30O4 24150-24-1

OCH3 H CH3 H3CO OCH3 H3CH H3CO

165 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

thrombinum alfa* thrombin alfa human thrombin (recombinant, glycoform α) coagulation promoting agent

thrombine alfa thrombine humaine (recombinante, glycoforme α) facteur de promotion de la coagulation

trombina alfa trombina humana (recombinante, glicoforma α) factor promotor de la coagulación

C1511H2342N418O436S15 869858-13-9

Light chain / Chaîne légère / Cadena ligera TFGSGEADCG LRPLFEKKSL EDKTERELLE SYIDGR 36 Heavy chain / Chaîne lourde / Cadena pesada IVEG SDAEIGMSPW 50 QVMLFRKSPQ ELLCGASLIS DRWVLTAAHC LLYPPWDKNF TENDLLVRIG 100 KHSRTRYERN IEKISMLEKI YIHPRYNWRE NLDRDIALMK LKKPVAFSDY 150 IHPVCLPDRE TAASLLQAGY KGRVTGWGNL KETWTANVGK GQPSVLQVVN 200 LPIVERPVCK DSTRIRITDN MFCAGYKPDE GKRGDACEGD SGGPFVMKSP 250 FNNRWYQMGI VSWGEGCDRD GKYGFYTHVF RLKKWIQKVI DQFGE 295 Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 9-155 64-80 209-223 237-267 Glycosylation site / Site de glycosylation / Posición de glicosilación Asn-89

tiliquinatinum tiliquinatine (2R)-2-{4-[(7-bromoquinolin-2-yl)oxy]phenoxy}propanoic acid antineoplastic

tiliquinatine acide (2R)-2-{4-[(7-bromoquinoléin-2-yl)oxy]phénoxy}propanoïque antinéoplasique

tiliquinatina ácido (2R)-2-{4-[(7-bromoquinolin-2-il)oxi]fenoxi}propanoico antineoplásico

C18H14BrNO4 445041-75-8

Br N O H CH3

O CO2H

totrombopagum totrombopag (4Z)-2-(3,4-dimethylphenyl)-4-(2-{2-hydroxy-3'-(1H-tetrazol-5-yl) [1,1'-biphenyl-3-yl]}hydrazinylidene)-5-methyl-2,4-dihydro- 3H-pyrazol-3-one thrombopoietin receptor agonist

totrombopag (4Z)-2-(3,4-diméthylphényl)-4-{2-[2-hydroxy-3'-(1H-tétrazol-5-yl) [1,1'-biphényl-3-yl]]diazanylidène}-5-méthyl-2,4-dihydro-3H-pyrazol- 3-one agoniste du récepteur de la thrombopoïétine

totrombopag (4Z)-2-(3,4-dimetilfenil)-4-{2-[2-hidroxi-3'-(1H-tetrazol-5-il)- [1,1'-bifenil-3-il]]hidrazinilideno}-5-metil-2,4-dihidro-3H-pirazol-3-ona agonista de los receptores de trombopoyetina

166 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C25H22N8O2 376592-42-6

N H3C HN N N N N N H N OH O

CH3 H3C

trabedersenum trabedersen 2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'- deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'- deoxy-P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thioadenylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy- P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxyadenosine antineoplastic

trabedersen 2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-2'- déoxy-P-thioguanylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'- déoxy-P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thioadénylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy- P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxyadénosine antinéoplasique

trabedersén 2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P-tioguanilil-(3'→5')-2'-desoxi- P-tioguanilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi- P-tioadenilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tioguanilil- (3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')- P-tiotimidilil-(3'→5')-2'-desoxi-P-tioadenilil-(3'→5')-P-tiotimidilil- (3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')- 2'-desoxi-P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'- desoxiadenosina antineoplásico

C177H225N60O94P17S17 925681-61-4

167 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

trelanserinum trelanserin 2-(7-fluoro-2-oxo-4-{2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin- 1-yl]ethyl}-1,2-dihydroquinolin-1-yl)acetamide serotonin receptor antagonist

trélansérine 2-(7-fluoro-2-oxo-4-{2-[4-(thiéno[3,2-c]pyridin-4-yl)pipérazin- 1-yl]éthyl}-1,2-dihydroquinolein-1-yl)acétamide antagoniste des récepteurs de la sérotonine

trelanserina 2-(7-fluoro-2-oxo-4-{2-[4-(tieno[3,2-c]piridin-4-il)piperazin-1-il]etil}- 1,2-dihidroquinolin-1-il)acetamida antagonista de los receptores de serotonina

C24H24FN5O2S 189003-92-7

H2N N O N N N F

tridecactidum* tridecactide alpha-1-13-corticotropin, human L-seryl-L-tyrosyl-L-seryl-L-methionyl-L-glutamyl-L-histidyl- L-phenylalanyl-L-arginyl-L-tryptophylglycyl-L-lysyl-L-prolyl-L-valine corticotropin-like activity

tridécactide alpha-1-13-corticotropine, humaine L-séryl-L-tyrosyl-L-séryl-L-méthionyl-L-glutamyl-L-histidyl- L-phénylalanyl-L-arginyl-L-tryptophylglycyl-L-lysyl-L-prolyl-L-valine activité corticotrope

tridecactida alfa-1-13-corticotropina, humana L-seril-L-tirosil-L-seril-L-metionil-L-glutamil-L-histidil-L-fenilalanil- L-arginil-L-triptofilglicil-L-lisil-L-prolil-L-valina actividad corticotropa

C75H106N20O19S 22006-64-0

HSer Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val OH 10

tropantiolum tropantiol 2-({[(1R,2R,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl]methyl}{2-[(2-sulfanylethyl)amino]ethyl}amino)ethanethiol chelating agent

tropantiol 2-({[(1R,2R,3S,5S)-3-(4-chlorophényl)-8-méthyl-8-azabicyclo[3.2.1] octan-2-yl]méthyl}{2-[(2-sulfanyléthyl)amino]éthyl}amino)éthanethiol chélateur

tropantiol 2-({[(1R,2R,3S,5S)-3-(4-clorofenil)- 8-azabiciclo[ 3.2.1]octan- 2-il]metil}{2-[(2-sulfaniletil)amino]etil}amino)etanotiol quelante

168 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

C21H34ClN3S2 189950-11-6

Cl H

N CH3 H

H H N SH HS N H

vatreptacogum alfa (activated)* vatreptacog alfa (activated) [158-aspartic acid, 296-valine, 298-glutamine]human coagulation factor VII activated, recombinant DNA origin blood coagulation factor

vatreptacog alfa (activé) [158-acide aspartique, 296-valine, 298-glutamine]facteur de coagulation VII humain activé, origine ADN recombinant facteur de coagulation sanguine

vatreptacog alfa (activada) [158-ácido aspártico, 296-valina, 298-glutamina]factor de coagulación VII humano activado ; origen ADN recombinante factor de coagulación sanguínea

C1981H3051N561O620S27 897936-89-9

Light chain / Chaîne légère / Cadena ligera ANAFLEELRP GSLERECKEE QCSFEEAREI FKDAERTKLF WISYSDGDQC 50 ASSPCQNGGS CKDQLQSYIC FCLPAFEGRN CETHKDDQLI CVNENGGCEQ 100 YCSDHTGTKR SCRCHEGYSL LADGVSCTPT VEYPCGKIPI LEKRNASKPQ 150 GR 152 Heavy chain / Chaîne lourde / Cadena pesada IVGGKDCP KGECPWQVLL LVNGAQLCGG TLINTIWVVS AAHCFDKIKN 200 WRNLIAVLGE HDLSEHDGDE QSRRVAQVII PSTYVPGTTN HDIALLRLHQ 250 PVVLTDHVVP LCLPERTFSE RTLAFVRFSL VSGWGQLLDR GATALVLQVL 300 NVPRLMTQDC LQQSRKVGDS PNITEYMFCA GYSDGSKDSC KGDSGGPHAT 350 HYRGTWYLTG IVSWGQGCAT VGHFGVYTRV SQYIEWLQKL MRSEPRPGVL 400 LRAPFP 406

Modified residues / Résidus modifiés / Residuos modificados H NH2 E HO2C H NH HO C 6-7-14-16-19-20-25-26-29-35 2 D 2 63 CO2H 4-carboxyGlu 3-hydroxyAsp HO2C CO2H OH

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 17-22 50-61 55-70 72-81 91-102 98-112 114-127 135-262 159-164 178-194 310-329 340-368

Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Ser-52 Ser-60 Asn-145 Asn-322

velimogenum aliplasmidum* velimogene aliplasmid plasmid DNA vector, expressing HLA-B7 and beta-2 microglobulin, driven by a Rous sarcoma virus promoter stimulates destruction of melanoma cells

vélimogène aliplasmide vecteur ADN plasmidique, contenant les gènes HLA-B7 et beta2- microglobuline, sous le contrôle du promoteur virus de sarcome de Rous stimule la destruction des cellules mélaniques

velimogén aliplásmido vector ADN de plásmído, que contiene los genes HLA-B7 y beta2- microglobulina, controlado por el promotor de virus del sarcoma de Rous estimula la destrucción de las células del melanoma

296251-72-4

169 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

voclosporinum voclosporin 1,11-anhydro[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl- N-methyl-L-valyl-[(2S,3R,4R,6E)-3-hydroxy-4-methyl- 2-(methylamino)nona-6,8-dienoyl][(2S)-2-aminobutanoyl]- N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine] immunosuppressant

voclosporine 1,11anhydro{L-alanyl-D-alanyl-N-méthyl-L-leucyl-N-méthyl-L-leucyl- N-méthyl-L-valyl-[(2S,3R,4R,6E)-3-hydroxy-4-méthyl- 2-(méthylamino)nona-6,8-diénoyl]-(2S)-2-aminobutanoyl- N-méthylglycyl-N-méthyl-L-leucyl-L-valyl-N-méthyl-L-leucyl] immunosuppresseur

voclosporina 1,11-anhidro[L-alanil-D-alanil-N-metil-L-leucil-N-metil-L-leucil-N-metil- L-valil-[(2S,3R,4R,6E)-3-hidroxi-4-metil-2-(metilamino)nona- 6,8-dienoil][(2S)-2-aminobutanoil]-N-metilglicil-N-metil-L-leucil-L-valil- N-methyl-L-leucina] inmunosupresor

C63H111N11O12 515814-01-4

CH2

CH3 H3C CH H CH 3 OH 3 H C 3 H3C H H H H H CH3 H3C N N N N N H O CH3 O CH3 O O H3C O O H CH H3C N 3 CH3 H3C N O OH3C O H H H H N N N N CH O 3 O H3CH HCH3 H H CH3 H3C H3C CH3

170 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Proposed International Non Proprietary Names (Prop. INN): List 31 (WHO Chronicle, Vol. 28, No. 3, 1974) p. 22 dimemorfanum dimemorfan replace graphic formula by the following

CH3 H N

H3C

Dénominations communes internationales proposées (DCI Prop.): Liste 31 (Chronique OMS, Vol. 28, No. 3, 1974) p. 22 dimemorfanum dimémorfane remplacer la formule développée par la suivante

CH3 H N

H3C

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 31 (Crónica de la OMS, Vol. 28, No. 3, 1974) p. 23 dimemorfanum dimemorfano sustitúyase la formúla désarollada por la siguiente

CH3 H N

H3C

171 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

Proposed International Non Proprietary Names (Prop. INN): List 71 Dénominations communes internationales proposées (DCI Prop.): Liste 71 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 71 (WHO Drug Information, Vol. 8, No. 2, 1994) p. 26 suprimáse insértese afovirseno afovirsén

Proposed International Non Proprietary Names (Prop. INN): List 75 Dénominations communes internationales proposées (DCI Prop.): Liste 75 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 75 (WHO Drug Information, Vol. 10, No. 2, 1996) p. 100 suprimáse insértese fomivirseno fomivirsén

Proposed International Non Proprietary Names (Prop. INN): List 77 Dénominations communes internationales proposées (DCI Prop.): Liste 77 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 77 (WHO Drug Information, Vol. 11, No. 2, 1997) p. 102 suprimáse insértese trecovirseno trecovirsén

Proposed International Non Proprietary Names (Prop. INN): List 80 Dénominations communes internationales proposées (DCI Prop.): Liste 80 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 80 (WHO Drug Information, Vol. 12, No. 4, 1998) p. 276 solimastatum solimastat insert the following CAS solimastat insérer le numéro de CAS suivant solimastat insértese el nombre del CAS siguiente 226072-63-5

Proposed International Non Proprietary Names (Prop. INN): List 81 Dénominations communes internationales proposées (DCI Prop.): Liste 81 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 81 (WHO Drug Information, Vol. 13, No. 2, 1999) p. 117 ganstigminum ganstigmine insert the following CAS ganstigmine insérer le numéro de CAS suivant ganstigmina insértese el nombre del CAS siguiente 457075-21-7

172 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

Proposed International Non Proprietary Names (Prop. INN): List 82 Dénominations communes internationales proposées (DCI Prop.): Liste 82 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 82 (WHO Drug Information, Vol. 14, No. 4, 1999) p. 268 cangrelorum cangrelor insert the following CAS number cangrélor insérer le numéro de CAS suivant cangrelor insértese el nombre del CAS siguiente 163706-06-7 p. 270 crobenetinum crobenetine insert the following CAS crobénétine insérer le numéro de CAS suivant crobenetina insértese el nombre del CAS siguiente 221019-25-6

p. 273 epitumomabum epitumomab insert the following CAS épitumomab insérer le numéro de CAS suivant epitumomab insértese el nombre del CAS siguiente 263547-71-3 p. 277 figopitantum figopitant insert the following CAS figopitant insérer le numéro de CAS suivant figopitant insértese el nombre del CAS siguiente 502422-74-4 p. 288 sulamserodum sulamserod insert the following CAS sulamsérod insérer le numéro de CAS suivant sulamserod insértese el nombre del CAS siguiente 219757-90-1

Proposed International Non Proprietary Names (Prop. INN): List 85 Dénominations communes internationales proposées (DCI Prop.): Liste 85 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 85 (WHO Drug Information, Vol. 15, No. 2, 2001) p. 98 suprimáse insértese alicaforseno alicaforsén

173 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

p. 121 pralnacasanum pralnacasan replace the action and use by the following pralnacasan remplacer les proprietés et indications par les suivantes pralnacasán sustitúyase el acción y uso por los siguientes

caspase inhibitor inhibiteur de la caspase inhibidor de la caspasa

Proposed International Non Proprietary Names (Prop. INN): List 86 Dénominations communes internationales proposées (DCI Prop.): Liste 86 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 86 (WHO Drug Information, Vol. 16, No. 1, 2002) p. 65 ozogamicinum ozogamicin insert the following CAS ozogamicine insérer le numéro de CAS suivant ozogamicina insértese el nombre del CAS siguiente 400046-53-9 p. 70 zoticasonum zoticasone insert the following CAS zoticasone insérer le numéro de CAS suivant zoticasona insértese el nombre del CAS siguiente 678160-57-1

Proposed International Non Proprietary Names (Prop. INN): List 87 Dénominations communes internationales proposées (DCI Prop.): Liste 87 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 87 (WHO Drug Information, Vol. 16, No. 2, 2002) p. 177 suprimáse insértese oblimerseno oblimersén

Proposed International Non Proprietary Names (Prop. INN): List 89 Dénominations communes internationales proposées (DCI Prop.): Liste 89 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 89 (WHO Drug Information, Vol. 17, No. 3, 2003) p. 186 suprimáse insértese aprinocarseno aprinocarsén

174 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

Proposed International Non Proprietary Names (Prop. INN): List 90 Dénominations communes internationales proposées (DCI Prop.): Liste 90 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 90 (WHO Drug Information, Vol. 18, No. 1, 2004) p. 49 certolizumabum pegolum certolizumab pegol replace the description by the following certolizumab pégol remplacer la description par la suivante certolizumab pegol sustitúyase la descripción por la siguiente

immunoglobulin, anti-(human tumor necrosis factor α) Fab' fragment (human mouse monoclonal CDP870 heavy chain, disulfide bonded with human mouse monoclonal CDP870 light chain), pegylated at Cys-227 on the heavy chain

immunoglobuline, anti-(facteur α de nécrose tumorale humain) ; (disulfure entre le fragment Fab' de la chaîne lourde et la chaîne légère de l'anticorps monoclonal de souris CDP870 humanisé), pégylée à Cyst-227 sur la chaîne lourde

inmunoglobulina, anti-(factor α de necrosis tumoral humano) fragmento Fab' (cadena pesada del anticuerpo monoclonal humanizado de ratón CDP870, disulfuro con la cadena ligera del anticuerpo monoclonal humanizado de ratón CDP870), pegilado Cis-227 de la cadena pesada

Proposed International Non Proprietary Names (Prop. INN): List 95 Dénominations communes internationales proposées (DCI Prop.): Liste 95 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 95 (WHO Drug Information, Vol. 20, No. 2, 2006) p. 117 aclidinii bromidum bromuro de aclidinio sustitúyase el nombre químico por el siguiente:

bromuro de (3R)-1-(3-fenoxipropil)-3-[(hidroxibis(tiofen-2-il)acetiloxi)]-1-2-butil- 3-{4-[3-(dibutilamino)propil]benzoil}- 1λ5-azabiciclo[2.2.2]octan-1-ilio p. 151 delete/supprimer/suprimáse insert/insérer/insértese

ticilimumabum tremelimumabum ticilimumab tremelimumab ticilimumab trémélimumab ticilimumab tremelimumab

175 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

Proposed International Non Proprietary Names (Prop. INN): List 96 Dénominations communes internationales proposées (DCI Prop.): Liste 96 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 96 (WHO Drug Information, Vol. 20, No. 4, 2006) p. 290 managlinatum dialanetilum managlinat dialanetil replace graphic formula by the following: managlinat dialanétil remplacer la formule développée par la suivante: managlinat dialanetilo sustitúyase la formúla désarollada por la siguiente:

H2N O O CH3 N S H O HN H C CH3 3 P NH O H C 3 H O CH3 H3C O

* Electronic structure available on Mednet: http://mednet.who.int/ * Structure électronique disponible sur Mednet: http://mednet.who.int/ * Estructura electrónica disponible en Mednet: http://mednet.who.int/

176 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

ANNEX 1

PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”) in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance with resolution WHA3.11 of the World Health Assembly, and in the substitution of such names.

Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such names shall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to the payment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“the Secretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted.

Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated members hereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidance in devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure2. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary.

Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposed international nonproprietary name is being considered. a) Such notice shall be given by publication in WHO Drug Information3 and by letter to Member States and to national and regional pharmacopoeia commissions or other bodies designated by Member States.

i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other persons known to be concerned with a name under consideration. b) Such notice shall:

i) set forth the name under consideration;

ii) identify the person who submitted the proposal for naming the substance, if so requested by such person;

iii) identify the substance for which a name is being considered;

iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed;

v) state the authority under which WHO is acting and refer to these rules of procedure. c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO.

Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date of publication, under article 3, of the name in WHO Drug Information.

1 See Annex 1 in WHO Technical Report Series, No. 581, 1975; proposed amendments are shown in bold-face type. The original text was adopted by the Executive Board in resolution EB15.R7 and amended in resolution EB43.R9.

2 See Annex 2.

3 Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization.

177 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in WHO Drug Information.

Such objection shall:

i) identify the person objecting;

ii) state his or her interest in the name;

iii) set forth the reasons for his or her objection to the name proposed.

Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its good offices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute name or names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists a formal objection thereto filed under article 5 which has not been withdrawn.

Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the Secretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as a recommended international nonproprietary name.

Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariat shall: a) request that it be recognized as the nonproprietary name for the substance; and b) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name and to prohibit registration of the name as a trademark or trade name.

Article 9 a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errors in medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name in pharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolved through other interventions than a possible substitution of a previously recommended international nonproprietary name, or in the event that a previously recommended international nonproprietary name differs substantially from the nonproprietary name approved in a significant number of Member States, or in other such extraordinary circumstances that justify a substitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interested person. Such proposals shall be submitted on the form provided therefore and shall:

i) identify the person making the proposal;

ii) state his or her interest in the proposed substitution; and

iii) set forth the reasons for the proposal; and

iv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort to resolve the situation, and the reasons why these other interventions were inadequate.

Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance with the General principles, which takes into account the pharmaceutical substance for which the new substitute international nonproprietary name is being proposed.

The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described in subsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the person bringing the proposal for substitution and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations).

In addition, the Secretariat shall request comments on the proposal from:

i) Member States and national and regional pharmacopoeia commissions or other bodies designated by Member States (by including a notice to that effect in the letter referred to in article 3(a), and

178 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

ii) any other persons known to be concerned by the proposed substitution.

The request for comments shall:

i) state the recommended international nonproprietary name that is being proposed for substitution (and the proposed substitute name, if provided);

ii) identify the person who submitted the proposal for substitution (if so requested by such person);

iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution;

iv) set forth the time within which comments will be received and the person and place to whom they should be directed; and

v) state the authority under which WHO is acting and refer to these rules of procedure.

Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of the request for comments. b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments received to the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, after consideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing the proposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previously recommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN Expert Group for further processing. Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed for substitution.

In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, the INN Expert Group will select a new international nonproprietary name in accordance with the General principles referred to in article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3 and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previously recommended international nonproprietary name and that Member States may wish to make transitional arrangements in order to accommodate existing products that use the previously recommended international nonproprietary name on their label in accordance with national legislation.

If, after consideration of the proposal for substitution and the comments received in accordance with the procedure described above, the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution do not agree that there are compelling reasons for substitution of a previously recommended international nonproprietary name, this name shall be retained (provided always that the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to be substituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and any other persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has been decided to retain the previously recommended international nonproprietary name (with a description of the reason(s) why the proposal for substitution was not considered sufficiently compelling).

Article 10 - A working process, intended to serve as a guide for the INN Expert Group in the implementation of this procedure, is attached hereto as an appendix.

179 Proposed INN: List 97 WHO Drug Information, Vol. 21, No. 2, 2007

ANNEX 2

GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently long and should not be liable to confusion with names in common use.

2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided.

These primary principles are to be implemented by using the following secondary principles:

3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibility of devising suitable INN for related substances, belonging to the new group.

4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name, e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”.

5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or the inactive base. For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of a quaternary substance and not in the amine-salt style.

6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable.

7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of “ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided.

8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration.

9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.2 Where a stem is shown without any hyphens it may be used anywhere in the name.

Latin English

-acum -ac anti-inflammatory agents, ibufenac derivatives -adolum -adol } analgesics -adol- -adol-} -astum -ast anti-asthmatic, anti-allergic substances not acting primarily as antihistaminics -astinum -astine antihistaminics -azepamum -azepam diazepam derivatives bol bol steroids, anabolic -cain- -cain- class I antiarrhythmics, procainamide and lidocaine derivatives -cainum -caine local anaesthetics

1 In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonpropriety Names for Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for, and the implications of, the change are fully discussed. The guiding principles were updated during the 13th consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARM S/NOM 928 13 May 1983, revised 18 August 1983).

2 A more extensive listing of stems is contained in the working document WHO/PSM/QSM/2006.3 which is regularly updated and can be requested from the INN Programme, WHO, Geneva.

180 WHO Drug Information, Vol. 21, No. 2, 2007 Proposed INN: List 97

cef- cef- antibiotics, cefalosporanic acid derivatives -cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives -conazolum -conazole systemic antifungal agents, miconazole derivatives cort cort corticosteroids, except prednisolone derivatives -coxibum -coxib selective cyclo-oxygenase inhibitors -entanum -entan endothelin receptor antagonists gab gab gabamimetic agents gado- gado- diagnostic agents, gadolinium derivatives -gatranum -gatran thrombin inhibitors, antithrombotic agents gest gest steroids, progestogens gli gli antihyperglycaemics io- io- iodine-containing contrast media -metacinum -metacin anti-inflammatory, indometacin derivatives -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoal substances, metronidazole derivatives -ololum -olol β-adrenoreceptor antagonists -oxacinum -oxacin antibacterial agents, nalidixic acid derivatives -platinum -platin antineoplastic agents, platinum derivatives -poetinum -poetin erythropoietin type blood factors -pril(at)um -pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory substances, ibuprofen derivatives prost prost prostaglandins -relinum -relin pituitary hormone release-stimulating peptides -sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-peptidic) -vaptanum -vaptan vasopressin receptor antagonists vin- vin- } vinca-type alkaloids -vin- -vin-}

ANNEXE 1

PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNES INTERNATIONALES RECOMMANDEES POUR LES SUBSTANCES PHARMACEUTIQUES1

L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédure exposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacement de telles dénominations.

Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions de remplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de telles propositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondants assumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peut être modifié de temps à autre.

Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignés sous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directives générales pour la formation de dénominations communes internationales pour les substances pharmaceutiques » reproduites ci-après2. La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent à s’écarter de cette règle.

1 Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975 ; les amendements proposés sont indiqués en caractères gras. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7 et amendé dans sa résolution EB43.R9.

2 Voir annexe 2.

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Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale est à l’étude. a) Cette notification est faite par une insertion dans WHO Drug Information1 et par l’envoi d’une lettre aux Etats Membres et aux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres.

i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autres personnes portant à la dénomination mise à l’étude un intérêt notoire. b) Cette notification contient les indications suivantes :

i) dénomination mise à l’étude;

ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne le demande ;

iii) définition de la substance dont la dénomination est mise à l’étude ;

iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom et adresse de la personne habilitée à recevoir ces observations et objections ;

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’OMS.

Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3).

Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3).

Cette objection doit s’accompagner des indications suivantes :

i) nom de l’auteur de l’objection ;

ii) intérêt qu’il ou elle porte à la dénomination en cause ;

iii) raisons motivant l’objection contre la dénomination proposée.

Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen par l’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénomination commune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée.

Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont été levées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que la dénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée.

Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale recommandée, le Secrétariat : a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; et b) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur cette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale.

1 Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé.

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Article 9 - a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs de médication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec une autre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risques d’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénomination commune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjà recommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres, ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationale recommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée sur la formule prévue à cet effet et doit s’accompagner des indications suivantes :

i) nom de l’auteur de la proposition ;

ii) intérêt qu’il ou elle porte au remplacement proposé ;

iii) raisons motivant la proposition ; et

iv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé des raisons pour lesquelles ces interventions ont échoué.

Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement, établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelle dénomination commune internationale de remplacement est proposée.

Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin au paragraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles).

De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition :

i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismes désignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), et

ii) toutes autres personnes portant au remplacement proposé un intérêt notoire.

La demande d’observations contient les indications suivantes :

i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et la dénomination de remplacement proposée, si elle est fournie) ;

ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ;

iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ;

iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir ces commentaires ; et

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.

Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans les quatre mois qui suivent la date de la demande d’observations. b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observations reçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition de remplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts des DCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il est nécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la proposition de remplacement au Groupe d’experts des DCI pour qu’il y donne suite.

Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une

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proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer.

Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour qu’il y donne suite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives générales mentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat en vertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas la même personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjà recommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants qui utilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législation nationale.

Si, après examen de la proposition de remplacement et des observations communiquées conformément à la procédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de la proposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer une dénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que le demandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissions nationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autres personnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a été décidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou des raisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative).

Article 10 - Une méthode de travail, destinée à servir de guide pour le Groupe d’experts des DCI en vue de la mise en œuvre de cette procédure, est jointe en appendice au présent texte.

ANNEXE 2

DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS COMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCES PHARMACEUTIQUES1

1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance et leur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjà couramment employées.

2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptibles d’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront être évitées dans la mesure du possible.

Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants :

3. Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de la possibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe.

1 Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix, compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances de synthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe des substances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies. Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril 1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983).

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4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un terme qui ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénac sodique».

5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acide actif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom de l’acide inactif (ou de la base inactive). En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée au cation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignation évoquant un sel aminé.

6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union.

7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de « th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité.

8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays.

9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI par l’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes de substances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segments- clés indiqués sans trait d’union pourront être insérés n’importe où dans une dénomination.

Latin Français

-acum -ac substances anti-inflammatoires du groupe de l’ibufénac -adolum -adol } analgésiques -adol- -adol- } -astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tant qu’antihistaminiques -astinum -astine antihistaminiques -azepamum -azépam substances du groupe du diazépam bol bol stéroïdes anabolisants -cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne -cainum -caïne anesthésiques locaux cef- céf- antibiotiques, dérivés de l’acide céphalosporanique -cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique -conazolum -conazole agents antifongiques systémiques du groupe du miconazole cort cort corticostéroïdes, autres que les dérivés de la prednisolone -coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase -entanum -entan antagonistes du récepteur de l’endothéline gab gab gabamimétiques gado- gado- agents diagnostiques, dérivés du gadolinium -gatranum -gatran antithrombines, antithrombotiques gest gest stéroïdes progestogènes gli gli antihyperglycémiants io- io- produits de contraste iodés -metacinum -métacine substances anti-inflammatoires du groupe de l’indométacine -mycinum -mycine antibiotiques produits par des souches de Streptomyces -nidazolum -nidazole substances antiprotozoaires du groupe du métronidazole -ololum -olol antagonistes des récepteurs β-adrénergiques -oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique -platinum -platine antinéoplasiques, dérivés du platine -poetinum -poétine facteurs sanguins de type érythropoïétine -pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine -profenum -profène substances anti-inflammatoires du groupe de l’ibuprofène prost prost prostaglandines

1 Une liste plus complète de segments-clés est contenue dans le document de travail WHO/PSM/QSM/2006.3 qui est régulièrement mis à jour et qui peut être demandé auprès du programme des DCI, OMS, Genève.

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-relinum -réline peptides stimulant la libération d’hormones hypophysaires -sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (non peptidiques) -vaptanum -vaptan antagonistes du récepteur de la vasopressine vin- vin- } alcaloïdes du type vinca -vin- -vin- }

ANEXO 1

PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNES INTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS1

La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionar denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo dispuesto en la resolución WHA3.11, como para sustituir esas denominaciones.

Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución de esas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estas propuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para la Secretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente.

Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en Farmacopea Internacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante designados como «el Grupo de Expertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas», anexos a este procedimiento.2 A menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto o fabricado y comercializado por primera vez esa sustancia farmacéutica.

Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto de denominación internacional. a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS3 y el envío de una carta a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros.

i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y a otras personas que tengan un interés especial en una denominación objeto de estudio. b) En esa notificación se incluirán los siguientes datos:

i) la denominación sometida a estudio;

ii) la identidad de la persona que ha presentado la propuesta de denominación de la sustancia, si lo pide esa persona;

iii) la identidad de la sustancia cuya denominación está en estudio;

iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y

v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

1 Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975; las modificaciones propuestas se indican en negrita. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 y modificado en la resolución EB43.R9.

2 Véase el anexo 2.

3 Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud.

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c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS la tenga en estudio.

Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3.

Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Esa objeción deberá acompañarse de los siguientes datos:

i) la identidad de la persona que formula la objeción;

ii) las causas que motivan su interés por la denominación; y

iii) las causas que motivan su objeción a la denominación propuesta.

Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podrá reconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS no seleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal, presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organización examine otra denominación o denominaciones sustitutivas.

Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las objeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3, que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada.

Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en el artículo 7, la Secretaría: a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; y b) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial.

Artículo 9 a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticas y/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación, prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potenciales errores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación común internacional recomendada anteriormente; en el caso de que una denominación común internacional recomendada anteriormente difiera considerablemente de la denominación común aprobada en un número importante de Estados Miembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacional recomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentarán en los formularios que se proporcionen a estos efectos e incluirán los siguientes datos:

i) la identidad de la persona que presenta la propuesta;

ii) las causas que motivan su interés en la sustitución propuesta;

iii) las causas que motivan la propuesta; y

iv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con el fin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes.

Entre esas propuestas podrá figurar una relativa a una nueva denominación común internacional sustitutiva, formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se proponga la nueva denominación común internacional sustitutiva.

La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que sea una persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones

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industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en el párrafo b) infra.

Además, la Secretaría solicitará observaciones sobre la propuesta:

i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que se refiere el párrafo a) del artículo 3), y

ii) a cualquier persona que tenga un interés especial en la sustitución propuesta.

Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos:

i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutiva propuesta, si se ha facilitado);

ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona);

iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar la propuesta de sustitución;

iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y

v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro meses siguientes a la fecha en que se realizó la solicitud de observaciones. b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentarios recibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado la propuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo de Expertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están de acuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaría remitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite. No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone.

En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, este grupo seleccionará una nueva denominación común internacional de conformidad con los Principios generales a los que se refiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que la Secretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendada anteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables a los productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación común internacional recomendada anteriormente que se haya sustituido.

En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidad con el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la persona que haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas para sustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre en el entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así como al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas o

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a otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación común internacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que la propuesta de sustitución no estaba respaldada por razones suficientemente poderosas).

Artículo 10 - A fin de proporcionar orientación al Grupo de Expertos en DCI para la aplicación del presente procedimiento, se incluye como apéndice un texto relativo al método de trabajo.

ANEXO 2

PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONES 1 COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS

1. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común.

2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar apropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas, fisiológicas, patológicas o terapéuticas para el paciente.

Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios:

3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de poder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo.

4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre del ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico».

5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo. Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombre del ácido o de la base inactivos. En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como componentes independientes de una sustancia cuaternaria y no como sales de una amina.

6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones.

7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugar de «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k».

8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideración preferente las denominaciones propuestas por la persona que haya descubierto las sustancias, o que fabrique y comercialice por primera vez una sustancia farmacéutica, así como las denominaciones ya adoptadas oficialmente en cualquier país.

9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando una partícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, en particular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente.2 Cuando una partícula aparece sin guión alguno, puede utilizarse en cualquier lugar de la palabra.

1 En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las Sustancias Farmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de las novedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a la denominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos. Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe se examinan en detalle las razones y consecuencias de este cambio. Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 de abril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983).

2 En el documento de trabajo WHO/PSM/QSM/2006.3, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones Comunes Internacionales, OMS, Ginebra, figura una lista más amplia de partículas.

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Latin Español

-acum -aco antiinflamatorios derivados del ibufenaco -adolum -adol ) analgésicos -adol- -adol- ) -astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica -astinum -astina antihistamínicos -azepamum -azepam derivados del diazepam bol bol esteroides anabolizantes -cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína -cainum -caína- anestésicos locales cef- cef- antibióticos, derivados del ácido cefalosporánico -cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico -conazolum -conazol antifúngicos sistémicos derivados del miconazol cort cort corticosteroides, excepto derivados de prednisolona -coxibum -coxib inhibidores selectivos de ciclooxigenasa -entanum -entán antagonistas del receptor de endotelina gab gab gabamiméticos gado- gado- agentes para diagnóstico derivados de gadolinio -gartranum -gatrán inhibidores de la trombina antitrombóticos gest gest esteroides progestágenos gli gli hipoglucemiantes, antihiperglucémicos io- io- medios de contraste iodados -metacinum -metacina antiinflamatorios derivados de indometacina -mycinum -micina antibióticos producidos por cepas de Streptomyces -nidazolum -nidazol antiprotozoarios derivados de metronidazol -ololum -olol antagonistas de receptores β-adrenérgicos -oxacinum -oxacino antibacterianos derivados del ácido nalidíxico -platinum -platino antineoplásicos derivados del platino -poetinum -poetina factores sanguíneos similares a la eritropoyetina -pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina -profenum -profeno antiinflamatorios derivados del ibuprofeno prost prost prostaglandinas -relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias -sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptorde angiotensina II -vaptanum -vaptán antagonistas del receptor de vasopresina vin- vin- ) alcaloides de la vinca -vin- -vin- )

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