WHO Drug Information Vol 22, No

WHO Drug Information Vol 22, No. 2, 2008 World Health Organization

WHO Drug Information

Contents Access to Medicines Lapatinib and hepatoxicity 96 Telbivudine and peripheral neuropathy 96 WHO prequalification: progress in 2007 79 International Nonproprietary Safety and Efficacy Issues Names Update on safety of heparin 84 International Nonproprietary Names Nicorandil-associated ulceration 85 for monoclonal antibodies: IFPMA Topiramate and other drugs causing proposal 97 glaucoma 86 Varenicline: serious psychiatric reactions 86 Montelukast : safety review 88 Regulatory Action and News Neurocognitive effects of chemotherapy 89 Dydrogesterone withdrawn for New MMRV vaccine recommendations 89 commercial reasons 108 Oseltamivir label updated with neuro- Enoxaparin contamination: batches psychiatric warning 90 recalled 109 Ketoconazole tablets: risk of hepato- Recombinant antihemophilic factor toxicity 90 approved 110 Alemtuzumab: infection-related deaths 91 Rotavirus vaccine approved 111 Mycophenolate mofetil: progressive New version of genetically engineered multifocal leukoencephalopathy 91 Factor VIIa approved 111 Modafinil: serious rash and psychiatric symptoms 92 Moxifloxacin: serious hepatic and skin International Pharmacopoeia reactions 92 Role of The International Pharmacopoeia Rimonabant: depression; psychiatric in quality assurance 113 reactions 93 Exenatide: risk of acute pancreatitis 94 Zanamivir: neuropsychiatric events 94 Proposed International Inosine ponophosphate dehydrogenase Nonproprietary Names: inhibitors: congenital anomalies 94 Strontium ranelate : life-threatening List 99 121 allergic reactions 95

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78 WHO Drug Information Vol 22, No. 2, 2008

Access to Medicines

WHO prequalification: products. This offers a considerable increase in the choice of prequalified progress in 2007 medicines for these diseases. The Prequalification Programme for The total number of prequalified products medicinal products is a service provided in 2007 was the lowest since 2001. The by the World Health Organization (WHO) main reasons for this are: to facilitate access to medicines that meet international unified standards of quality, • decreasing number of new submissions; safety and efficacy for HIV/AIDS, malaria, tuberculosis and reproductive health. • submitted dossiers did not include sufficient evidence to prove quality, Work is carried out through: safety and efficacy of products; and • stringent assessment of pharmaceutical • little additional substantive evidence product dossiers; was provided in support of dossiers previously submitted. • inspection of pharmaceutical manufacturing sites (both for finished dosage Certain product groups are urgently in forms and active pharmaceutical ingre- need of expansion to increase available dients) and contract research organiza- treatment options, i.e., second-line anti- tions (CROs); tuberculosis and paediatric antiretroviral combination products. In 2007, only one • prequalification of pharmaceutical antituberculosis treatment submission quality control laboratories (QCLs); and and two new submissions for paediatric • advocacy for medicines of assured antiretrovirals were presented for WHO quality. Prequalification.

The Programme also provides high-level In the past year, the number and quality training, capacity building and technical of product dossiers submitted for assess- assistance to stakeholders from both the ment was very uneven. Conversely, a private and public sectors. The Bill & considerable number of new applicants Melinda Gates Foundation as well as approached WHO. However, most of the UNITAID are currently the principle newcomers have limited or no experience financial supporters of the WHO Prequali- in production to international standards fication Programme. and are not yet capable of generating the required evidence. The manufacturing New prequalified products conditions and quality specifications presented for reproductive health and Twenty-one products were added to the list antimalarial products were particularly of prequalified medicines in 2007 – all but poor. one being generics. The number of prequalified medicines now stands at 156. Efforts needed to reach A major achievement in 2007 was the prequalification status prequalification of five new products to The products prequalified in 2007 were, treat tuberculosis and three antimalaria on average, under assessment and

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Summary of activities in 2007

The WHO Prequalification Programme:

• Prequalified a total of 21 medicinal products, including 5 anti-tuberculosis and 3 anti-malarial medicines • Intensified and widened the scope of prequalification of quality control laboratories • Doubled the number of training workshops for capacity building in resource- limited countries • Organized 10 technical assistance missions for manufacturers to support improvements in the quality of their products • Planned and implemented a comprehensive sampling and testing programme • Developed guidelines and standards to facilitate global quality assurance activities, including pharmacopoeial monographs and chemical reference substances • Undertook special efforts to facilitate development of paediatric formulations • Recruited additional full-time staff to maintain sustainability and improve perform- ances of prequalification process • Streamlined the process between receiving a complete dossier and the first assessment or inspection of manufacturing sites • Developed tools to increase transparency and allow monitoring of the prequalification process adjustment for two years before attaining Maintaining the list compliance with international standards. of prequalified medicines During this period, eight to nine assess- Inclusion in the list does not mean that ment sessions and five inspections were the prequalified status of a product lasts required before the ultimate positive forever. All prequalified medicines have conclusions were reached. Thus, consid- to be checked regularly in order to ensure erable time and resources are needed that any changes undertaken by manu- from applicants, as well as dedication to facturers do not undermine the quality, implementing the necessary corrective safety and efficacy of the products. action, to meet international quality standards. In order to reach this objective, WHO assesses variations in manufacture and All involved stakeholders agree and carries out random quality control tests of understand that expansion of the list of prequalified medicines, as well as re- prequalified medicines can only be inspections of manufacturing sites. As the realized if capacity building and technical prequalified products list is constantly assistance activities increase in resource- growing, maintaining and updating the limited countries. Therefore, such actions information becomes increasingly impor- have become one of the core objectives tant in order to ensure the quality and of the Prequalification Programme. safety of the medicines.

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Training Workshops organized in 2007

Date Location Content of training

16–20 April Cape Town, Pharmaceutical development with a South Africa focus on paediatric medicines

6–7 June Cairo, Egypt WHO Prequalification Programme – introduction for EMRO countries

25–27 June Kiev, Ukraine Dissolution, pharmaceutical product inter-changeability and biopharma- ceuticals classification system

10–14 September Dar Es Sallam, Assessment of dossiers based on Tanzania WHO Prequalification guidelines for staff of East Africa Community national medicine regulatory authorities

15–19 October Tallinn, Estonia Pharmaceutical development with a focus on paediatric medicines

5–9 November Jiaxing, China Pharmaceutical quality, Good Manufac turing Practice and bioequivalence with a focus on anti-tuberculosis products

26–29 November Rabat, Morocco Quality assurance, Prequalification and quality control in quality control laboratories

10–14 December Dakar, Senegal Good Manufacturing Practice training course for countries of francophone Africa

5–7 December Dar Es Sallam, Quality assurance, Prequalification and Tanzania development of standards in quality control laboratories

Capacty building groups, including staff from regulatory for regulatory authorities agencies and quality control laboratories, Recognizing the importance of capacity and for manufacturers. Such training building through training and hands-on includes group sessions as well as practice, the WHO Prequalification communication between involved parties, programme organized nine training such as manufacturers and the present- courses in 2007 and co-organized four ers, who are themselves part of the training activities together with other assessment or inspection teams working partners in nine different countries. with the Prequalification Programme. These exercises offered tuition on gen- In 2007, four national regulatory experts eral or specific technical issues for larger from Ethiopia, Tanzania, Uganda and

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Zimbabwe were offered a full-time posi- Dossier assessments tion at WHO for three months. The and expert advice objective was to create a rotational In 2007, six assessment sessions were network between WHO and resource- organized at the UNICEF Supply Division limited countries, increase capacity in Copenhagen where the product dossi- building of national regulatory authorities ers are received and stored. In total, 39 and enhance information exchange external assessors from both well and between all parties. less resourced regulatory authorities participated in the assessment sessions. Technical assistance It is worth noting that regulators from the to manufacturers WHO Africa Region have been especially Since 2006, the WHO Prequalification active in the process. programme has provided coordinated technical assistance aimed at resolving In addition to regular assessment acti- specific practical problems encountered vities, considerable increase in expert by manufacturers or quality control scientific advice provided to applicants laboratories. Assistance is given by a was observed in 2007 – a total of 16 qualified professional in the form of an bioequivalence study protocols were audit and training in technical or regula- reviewed, with more than 80 bioequiva- tory areas. lence queries answered, and 35 separate quality issues handled by the respective In 2007 alone, the WHO Prequalification expert panels. programme provided a total number of 13 technical assistance sessions in nine Inspections different countries, compared to six in A total of 45 inspections were carried out four countries in 2006. in seven different countries in 2007, with 35 taking place in India. As in the previ- To avoid conflict of interest, WHO uses a ous year, considerable assistance with pool of specialists working either for inspections was received from national nonprofit organizations or acting as inspectorates belonging to The Pharma- individual technical consultants unrelated ceutical Inspections Convention and to prequalification activities. These Pharmaceutical Inspection Cooperation experts are not involved in assessments Scheme (jointly referred to as PIC/S). As and inspections. in 2006, France, was the leading country in terms of providing inspection support.

Technical assistance organized by WHO Prequalification Programme in 2007

Date Location Content of technical assistance 6–9 February Ukraine Stability studies and GMP 5–10 March China GMP of manufacture under aseptic conditions 26 March – 2 April Cambodia GMP of packaging combination products 1–5 May Zimbabwe GMP of antiretroviral products 20–26 May India Manufacturing process validation and GMP 17–29 July Cambodia GMP of packaging combination products 23–29 August Bangladesh Pharmaceutical engineering and GMP 04–09 November Zimbabwe GMP of antiretroviral products 17–21 December India Manufacturing process validation and GMP 17–22 December China GMP of manufacture under aseptic conditions

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Prequalification assessment and inspection statistics: 2007 Dossier Assessment Assessment sessions in Copenhagen 6 Total number of assessment days 42 Total number of assessment reports 463 Assessment reports on HIV/AIDS products 298 Assessment reports on TB products 100 Assessment reports on malaria products 54 Assessment reports on reproductive health products 11

Inspections Manufacturing sites of finished product manufacturers 26 Manufacturing sites of active pharmaceutical ingredients 6 Contract research organizations 13 National pharmaceutical quality control laboratories 1

Prequalification of quality Developments to the website at http:// control laboratories www.who.int/prequal include: One laboratory was prequalified in 2007, while 12 laboratories expressed interest • creation of a public tool to monitor in prequalification but only seven submit- dossier status of products currently ted the required information file. The under evaluation; Programme carried out six pre-audit visits • more and better guidance for applicants; and inspectors concluded that all applicants needed training and technical • new invitations to manufacturers of HIV, assistance. antimalaria, antituberculosis and reproductive health products; Strengthening and transparency of activities • publication of the annual report in six In January 2007, there were five full-time languages; professional staff members working for • creation of a section in Chinese to the WHO Prequalification Programme — accommodate the translated documents a number that increased to 12 by the end on prequalification; and of the year. A database to log and track dossier assessment and inspections was • creation of a searchable and custom- developed and became operational in ized registry of prequalified medicines. 2007.

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Safety and Efficacy Issues

Update on safety of heparin tests are now mandatory for batch release of all heparin API preparations in World Health Organization — On 17 the USA (3). January 2008, Baxter Healthcare Corpo- ration began voluntary recall of nine lots In Germany, 80 or more recent cases of of heparin sodium in the USA. The ad- similar adverse events (no deaths) verse events are described as acute relating to specific batches of heparin allergic-type reactions and have been products manufactured by Rotexmedica documented by the US Centers for GmbH have also been reported. Disease Control (CDC) (1). The number Rotexmedia initiated a recall on several of recent adverse reactions associated batches of heparin injection in early with the Baxter heparin preparations is March 2008 (4). The origin of the heparin over 700, including 19 deaths. The US in these products is the Changzhou Food and Drug Administration (FDA) and Quianhong Bio Pharma Co. Ltd., China, Baxter are conducting an investigation and the Yantai Dongcheng Biochemicals into these clusters of adverse reaction Co., China. reports. Further recalls of heparin products from The active pharmaceutical ingredient other suppliers have followed more (API) for the batches of heparin associ- recently, in the USA and elsewhere. ated with adverse reactions originated Heparin is on the WHO Model List of from the Scientific Protein Laboratories Essential Medicines, and WHO distrib- (SPL) Changzhou facility in China. The utes the 5th International Standard FDA investigation included inspections of Heparin for measurement of the potency the manufacturing plants in China and the of unfractionated heparin preparations USA. The FDA’s report of its inspection of according to methods outlined in the the Changzhou SPL manufacturing plant International Pharmacopoeia. Other was critical of several aspects of its WHO International Standards for heparin processes. are the low molecular weight heparin standards for both biological activity and The US FDA has found that heparin for molecular weight calibration. All the batches associated with adverse reac- WHO International Standards for heparin tions contain 5–20% by weight of a have been found to be free of contamina- “heparin-like compound which is not tion according to criteria defined in the heparin” contaminant. The contaminant most recent version of the FDA’s “Impu- has been identified as an oversulfated rity evaluation of Heparin Sodium by chondroitin sulfate (2). The FDA has NMR Spectroscopy” (5). published two screening methods which can identify the presence of the heparin- Adverse reactions to heparin products like contaminant oversulfated chondroitin should be reported to the appropriate sulfate; one of them involves proton National Regulatory Authority. WHO has nuclear magnetic resonance (NMR) a programme on International Drug spectroscopy, and the other involves Monitoring, co-ordinated by the Uppsala capillary electrophoresis (CE). These Monitoring Centre, Uppsala, Sweden (6).

84 WHO Drug Information Vol 22, No. 2, 2008 Safety and Efficacy Issues

WHO can offer advice and help to na- Subsequently, ulceration has been tional regulatory authorities in countries reported at other sites, including anal, with limited resources for the characteri- perianal, vulvar, perivulvar, gastrointesti- zation of suspect batches of heparin API, nal and parastomal tissues, and various including testing by NMR and CE as cutaneous sites, including the lower recommended by the FDA, through the anterior leg, natal cleft, umbilicus and WHO Collaborating Centre for Biological areas affected by flexural psoriasis; Standards. ulcers may occur at multiple sites (2, 3). The reaction occurs rarely, appears to be The WHO Expert Committee on Specifi- dose-related and the time to ulcer onset cations for Pharmaceutical Preparations, may be up to months after starting which oversees the activities related to nicorandil. The ulcers are persistent, The International Pharmacopoeia, to- deep and ‘punched out’ in appearance, gether with the WHO Expert Committee with non-specific inflammatory histology. on Biological Standardization, will review Their pathogenesis remains unclear. the above information as well as appropriate validated tests for impurity evaluation Unless nicorandil is recognized as a of unfractionated heparin. potential cause and the drug withdrawn, the ulcers are likely to persist despite References other treatment. Conservative ulcer management is ineffective and surgery 1. http://www.cdc.gov/mmwr/pdf/wk/mm57 may exacerbate the tissue damage. e201.pdf Typically any discomfort resolves quickly 2. http://www.fda.gov/bbs/transcripts/2008/ after nicorandil is withdrawn, although heparin_transcript_ 031908.pdf healing may take considerably longer.

3. http://www.fda.gov/cder/drug/infopage/ Seven of 51 reports received by the heparin/default.htm Therapeutic Goods Administration (TGA) 4. http://www.rotexmedica. com/index.php? for nicorandil describe ulceration. Six of page_id=18 the seven reports described tongue or mouth ulcers. Failure to recognize 5. http://www.fda.gov/cder/drug/infopage/ nicorandil-induced ulceration can lead to heparin/Heparin_NM_method.pdf substantial morbidity, inappropriate 6. http://www.who-umc.org/DynPage.aspx investigation and treatment, and unnec- essary surgery. 7. World Health Organization. http:// www.who.int/medicines and http://www.who. Extracted from Australian Adverse Drug int/biologicals Reactions Bulletin, Volume 27, Number 2, April 2008 Nicorandil-associated ulceration References Australia — Nicorandil (Ikorel®) is a 1. Reichert S et al. Major aphthous stomatitis synthetic nicotine derivative, which induced by nicorandil. Eur J Dermatol 1997; 7: causes arterial and venous dilatation. 132–3. It is indicated for the treatment of chronic 2. Watson A et al. Nicorandil induced anal stable angina pectoris at a dose of ulceration. Lancet 2002; 360: 546–7. 10–20 mg daily. Nicorandil-associated ulceration was 3. McKenna DJ et al. Nicorandil-induced leg ulceration. Br J Dermatol 2007; 156: 394–6. initially reported in oral mucosa (1).

85 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 2, 2008

Topiramate and other drugs proposed for this reaction, but because causing glaucoma pupillary block is not involved, pilocarpine and iridotomy are generally ineffective. Australia —Topiramate is an antiepileptic Permanent vision loss can occur if the indicated for either monotherapy or add- condition is not managed appropriately on therapy in adults and in children aged (3). Of note is that migraine itself may two years and over; and for the prophy- cause eye pain and it is important that laxis of migraine in adults. It has an non-migraine causes should be consid- authority required Pharmaceutical Ben- ered in patients treated with topiramate efits Schedule (PBS) listing for the for migraine, who present with eye pain. treatment of epilepsy, and was recently PBS-listed as a third-line agent for the Extracted from Australian Adverse Drug prophylaxis of migraine. Reactions Bulletin, Volume 27, Number 2, April 2008 Topiramate has been rarely associated with the development of angle-closure References glaucoma. To date, the Therapeutic 1. Lin J, Fosnot J and Edmond J. Bilateral Goods Administration (TGA) has received angle closure glaucoma in a child receiving 11 reports of glaucoma associated with oral topiramate. Journal of American Associa- the use of topiramate out of 175 total tion for Pediatric Ophthalmology and Strabis- reports for the drug, Five patients had mus [JAAPOS] 2003; 7: 66-68. recovered at the time of reporting, three had not yet recovered, and recovery 2. Fraunfelder FW et al. Topiramate-associ- status was unknown in the other three. ated acute, bilateral, secondary acute-angle closure glaucoma. Ophthalmology 2004 Although all of these cases have involved Jan;111(1):109-11. adults, a literature report has described 3. Levy et al. Topiramate-induced bilateral bilateral angle-closure glaucoma present- angle-closure glaucoma. Can J Ophthalmol ing as headache, nausea, and fatigue in 2006; 41: 221-225. a five year old girl 10 days after starting topiramate (1). Varenicline: serious A published review of reports of ocular psychiatric reactions reactions to topiramate included 86 cases of acute glaucoma, 83 of which were Canada — Varenicline tartrate bilateral (2). In this series, time to onset (Champix®) has been marketed in was one to 49 days after starting Canada since April 2007 and is indicated topiramate, with 85% of cases occurring for smoking-cessation treatment in adults in the first two weeks of treatment. in conjunction with smoking-cessation Permanent vision loss was described in counselling (1). The efficacy of seven reports. Topiramate was also varenicline in smoking cessation is associated with a number of other ocular believed to be a result of the drug’s partial adverse effects, including acute myopia, agonist activity at the nicotinic acetylcho- suprachoroidal effusions, periorbital line receptor. By binding to these oedema, and scleritis (2). receptors, varenicline induces 2 results (2). First, it signals the release of Management of topiramate-induced dopamine and creates similar reinforcing glaucoma involves immediate cessation effects, but not to the full extent that of topiramate and urgent medical treat- nicotine does because of its partial ment of the glaucoma as required. A binding of the receptor (2). Second, it acts number of mechanisms have been as a physical antagonist by binding to the

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Table 1: Summary of reports of aggression, depression and suicidal tendency suspected of being associated with varenicline submitted to Health Canada from 1 April 2007 to 23 Noveber 2007*

Case/Patient History of Adverse reaction(s)† Time to Outcome after age/sex psychiatric onset of discontinuation condition reaction, of varenicline d‡

1. 51/F No Aggressiveness 4 Unknown

2. 65/M Yes Aggressiveness 36 Recovered

3. 46/M Yes Depression 1 Recovered

4. 55/F Unknown Depression <2 Recovered

5. 64/M No Depression 2 Recovered

6. NA/F Yes Depression <42 NA§

7. 64/F Unknown Depression Unknown NA¶

8. 33/F No Suicidal tendency 11 Unknown

9. 55/F Unknown Suicidal tendency <14 Unknown

10. 53/F No** Suicidal tendency/ <29 Recovered depression

11. 30/F Unknown Suicidal tendency/ <31 Unknown depression

12. 46/M No Suicidal tendency/ <32 Recovered depression

13. 54/M No Suicidal tendency/ <72 Recovered depression

14. 58/F Yes Suicidal tendency/ <13 Recovered depression/anger

Note: NA = not available.

* These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration. † Terms are listed according to the World Health Organization Adverse Reaction Terminol- ogy (WHOART). ‡ Estimated from the beginning of treatment. § At the time of reporting, the patient was still taking varenicline and had not yet recovered. ¶ The onset of depression was after the discontinuation of the drug. ** Family history of depression was reported.

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nicotine receptor and by blocking the 2. Stack NM. Smoking cessation: an overview effects of nicotine or a nicotine-replace- of treatment options with a focus on vareni- ment agent (2). cline. Pharmacotherapy 2007;27(11): 1550–7. Smoking cessation with or without treat- 3. Freedman R. Exacerbation of schizophrenia ment is associated with various symp- by varenicline. Am J Psychiatry 2007;164(8): toms such as depressed mood, insomnia, 1269. irritability, frustration or anger, and anxiety (1). From 1 April to 23 November 2007, 4. Kohen I, Kremen N. Varenicline-induced manic episode in a patient with bipolar Health Canada received 107 reports of disorders. Am J Psychiatry 2007; 164(8): adverse reactions (ARs) suspected of 1269–70. being associated with varenicline. Of these reports, 46 described psychiatric ARs of which 14 reported cases of Montelukast : safety review aggression, depression or suicidal idea- United States of America — The Food tion (table 1). The remaining cases of and Drug Administration (FDA) is investi- psychiatric disorders included ARs such gating a possible association between the as amnesia, abnormal dreams, anxiety, use of montelukast (Singulair®) and insomnia, abnormal thinking and somno- behavior/mood changes, suicidality and lence. suicide. Montelukast is a leukotriene receptor antagonist used to treat asthma The impact of a smoking-cessation pro- and symptoms of allergic rhinitis, and to duct with partial nicotinic-receptor agonist prevent exercise-induced asthma. properties in patients with underlying psychiatric illness is unknown, and care Over the past year, the manufacturer has should be taken with these patients (1). updated the prescribing and patient Two case reports recently described the information to include the following post- exacerbation of schizophrenia in one marketing adverse events: tremor (March patient (3) and a manic episode in a 2007), depression (April 2007), suicidality patient with bipolar disorder taking vare- (October 2007), and anxiousness (Febru- nicline (4). ary 2008).

The Canadian Product Monograph for FDA is working with the manufacturer to varenicline was recently revised to further evaluate a possible link between indicate that there have been postmarket the use of Singulair® and behavior/mood reports of depressed mood, agitation, changes, suicidality and suicide. Until changes in behaviour, suicidal ideation further information is available, healthcare and suicide (1). The product monograph professionals and caregivers should states that not all patients had known pre- monitor patients for suicidality or changes existing psychiatric illness and not all had in behavior and mood. completely discontinued smoking (1). Other leukotriene modifying medications Extracted from Canadian Adverse Reac- include zafirlukast (Accolate®), which is tion Newsletter, Volume 18, Issue 2, April also a leukotriene receptor antagonist 2008 and zileuton (Zyflo® and Zyflo CR®), which is a leukotriene synthesis inhibitor. References FDA is reviewing postmarketing reports it has received of behavior/mood changes, 1. Champix (varenicline tartrate tablets) [product monograph]. Kirkland (QC): Pfizer suicidality and suicide and will assess Canada Inc; 2007. whether further investigation is warranted.

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Reference: Information from FDA dated 27 the risk for febrile seizures among chil- March 2008 at http://www.fda.gov/medwatch dren aged 12—23 months after administration of the combination measles, Neurocognitive effects of mumps, rubella, and varicella (MMRV) chemotherapy vaccine (ProQuad®). ACIP updated recommendations remove ACIP’s previ- Australia —There is growing evidence ous preference for administering combi- that some patients who survive cancer nation MMRV vaccine over separate can suffer neurocognitive impairment injections of equivalent component after chemotherapy. vaccines (i.e., measles, mumps, and rubella [MMR] vaccine and varicella Although the symptoms are generally vaccine). subtle and improve after ceasing chemotherapy, for some survivors the symptoms The combination tetravalent MMRV are sustained and can impact significantly vaccine was licensed by the Food and on their quality of life. Some studies have Drug Administration (FDA) on 6 Septem- reported that 15–50% of patients have ber 2005, for use in children aged 12 cognitive impairment after chemotherapy months–12 years (1). MMRV vaccine can for solid tumours. Areas most affected are be used in place of trivalent MMR vaccine usually attention, concentration, verbal and monovalent varicella vaccine to and visual memory and processing implement the recommended 2-dose speed. vaccine policies for prevention of measles, mumps, rubella, and varicella (1, 2). Studies published in the past few years The first vaccine dose is recommended at report that up to 30% of patients with age 12–15 months and the second at age solid tumours may have cognitive impair- 4–6 years. ment before receiving chemotherapy. It is likely that the regimen, dose and In MMRV vaccine prelicensure studies, duration of chemotherapy influence the an increased rate of fever was observed incidence and severity of cognitive 5–12 and 0–42 days after the first vaccine impairment. Studies have found higher dose, compared with administration of rates of cognitive dysfunction in patients MMR vaccine and varicella vaccine at the receiving high doses of chemotherapy same visit (3, 4). Because of the known compared to those on standard doses. association between fever and febrile There are no proven interventions to seizures (5), CDC and Merck initiated prevent impairment and the mainstay of postlicensure studies to better understand therapy is to treat any depression and the risk for febrile seizures that might be anxiety. associated with MMRV vaccination.

Reference: Australian Prescriber Media ACIP also recommended establishing a Release, 4 February 2008 at http:// www.tga.gov.au work group to conduct in-depth evaluation of the findings regarding the increased risk for febrile seizures after the first dose New MMRV vaccine of MMRV vaccine to present for consid- recommendations eration of future policy options. CDC, United States of America — On 27 FDA, and ACIP will communicate updates February 2008, new information was and implement further necessary actions presented to the Advisory Committee on based on these evaluations (6). Immunization Practices (ACIP) regarding

89 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 2, 2008

References Reference: Physician’s First Watch, 5 March 2008. 1. CDC. Licensure of a combined live attenu- ated measles, mumps, rubella, and varicella Ketoconazole tablets: vaccine. MMWR 2005;54:1212—3. risk of hepatotoxicity 2. CDC. Prevention of varicella: recommendations of the Advisory Committee on Immuniza- United Kingdom — Following a system- tion Practices (ACIP). MMWR 2007;56(No. atic review of all available data, the RR-4). manufacturer of ketoconazole (Nizoral ®) tablets has released information on a 3. Shinefield H, Black S, Digilio L, et al. Evaluation of a quadrivalent measles, mumps, change to the Summary of Product rubella and varicella vaccine in healthy Characteristics (SmPC) because of a risk children. Pediatr Infect Dis J 2005;24:665—9. of serious hepatotoxicity and the availabil- ity of other effective antifungal treatments. 4. Merck & Co., Inc. ProQuad® (measles, Nizoral® tablets are now indicated for: mumps, rubella, and varicella [Oka/Merck] virus vaccine live) [package insert]. • Treatment of dermatophytosis and Whitehouse Station, NJ: Merck & Co., Inc.; 2005. Malassezia (previously called Pityrosporum) folliculitis that cannot be 5. Seizures in childhood. In: Kliegman RM, treated topically because of the site, Behrman RE, Jenson HB, Stanton BF, eds. extent of the lesion or deep infection of Nelson textbook of pediatrics. 18th ed. the skin, in patients resistant to, or Philadelphia, PA: Saunders; 2007:2457—75. intolerant of, fluconazole, terbinafine 6. Update: Recommendations from the and itraconazole. Advisory Committee on Immunization Prac- tices (ACIP) Regarding Administration of • Treatment of chronic mucocutaneous Combination MMRV Vaccine. MMWR Morbid- candidiasis, cutaneous candidiasis, and ity & Mortality Weekly Report. March 14, oropharyngeal candidiasis that cannot 2008. 57(10);258-260 be treated topically because of the site, extent of the lesion or deep infection of Oseltamivir label updated with the skin, in patients resistant to or neuropsychiatric warning intolerant of both fluconazole and itraconazole. United States of America —The product label for oseltamivir phosphate (Tamiflu®) In addition to the existing drug interac- has been revised to include a warning tions and contraindications, several other about possible neuropsychiatric events. drugs have been added to the list of The updated label is based on recom- contraindicated drugs, including: diso- mendations from the agency’s Pediatric pyramide; sertindole; nisoldipine; eplere- Advisory Committee meeting in Novem- none; and ergot alkaloids such as di- ber 2007. hydroergotamine, ergometrine (ergono- vine), ergotamine and methylergometrine Postmarketing reports indicate that some (methylergonovine) patients with influenza who were receiving oseltamivir had delirium and abnormal Very rare cases of serious hepatic toxic- behavior, leading to injury and even ity, including cases with a fatal outcome death. Most of the cases occurred in or requiring liver transplantation, have children and in Japan. The label now occurred with the use of oral ketocona- cautions clinicians to monitor their pa- zole. Some patients had no obvious risk tients for abnormal behavior when taking factors for liver disease. the drug.

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The risk of serious hepatic toxicity in- in this trial are the result of a prolonged creases with longer duration of treatment; period of immunosuppression resulting courses of greater than 10 days should from the sequencing of these drugs only be given after full consideration of without sufficient time for recovery, as the extent of treatment response and the well as other factors specific to this trial. risk benefit of continuing treatment. Liver function must be monitored in all patients The five fatal infections were reported as: receiving treatment with Nizoral® tablets. viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus The following Postmarketing adverse infection and Pneumocystis jiroveci drug reactions have been added: anaphy- pneumonia, all in patients who achieved lactoid and anaphylactic reactions; a complete response after induction angioneurotic oedema; adrenocortical therapy. insufficiency; cirrhosis, the reporting rate being very rare. References: Reference: Communication from Janssen- 1. Communication from Bayer Schering Cilag Ltd January 2008 \\mhralonfs01\home$\ Pharma AG and Genzyme Europe BV at http:/ tilstonec\Website\Feb 2008\Nizoral DDL.doc /www.mhra.gov.uk on the Medicines and Healthcare products Regulatory Agency (MHRA) website at http:// 2. Lin TS, Donohue KA, Lucas MS, Byrd JC, www.mhra.gov.uk/Safetyinformation Bengtson EM, Peterson BL, Larson RA (Cancer and Leukemia Group B USA). Consolidation therapy with subcutaneous (SC) Alemtuzumab: infection- alemtuzumab results in severe infections related deaths toxicity in previously untreated CLL patients who achieve a complete response (CR) after United Kingdom — Bayer Schering fludarabine and rituximab (FR) induction Pharma AG and Genzyme Europe BV therapy: Interim Satefy Analysis of the CALGB have informed physicians of six infection- Study 10101. Blood 2007 Nov;110(11): 232a– related deaths, reported from a trial 233a, [Abstract 755] (CALGB10101) in which previously untreated, symptomatic B-cell chronic 3. CALGB10101 abstract available online at lymphocytic leukemia (CLL) patients were http://www.hematology.org. treated with fludarabine and rituximab followed by alemtuzumab for remission Mycophenolate mofetil: consolidation. progressive multifocal leukoencephalopathy Alemtuzumab (MabCampath®) is approved for the treatment of patients with European Union — In agreement with B-cell chronic lymphocytic leukaemia (B- the European Medicines Agency (EMEA), CLL) for whom fludarabine combination the manufacturer of mycophenolate chemotherapy is not appropriate and mofetil (CellCept®) has advised physi- should not be used as consolidation cians of new safety information. therapy following induction with CellCept® has been on the market for fludarabine + rituximab outside of a over 10 years, as an immunosuppressive clinical trial. agent indicated in combination with ciclosporin and corticosteroids. Fludarabine, rituximab and alemtuzumab all have known immunosuppressive Isolated cases of progressive multifocal properties, and it is possible that the fatal leukoencephalopathy (PML) have been infectious complications which occurred reported in patients receiving CellCept®.

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The case reports have been associated Modafinil should be discontinued at the with confounding factors in particular the first sign of rash and not restarted nature of the underlying disease, con- unless the rash is clearly not drug- comitant immunosuppression and the related. latency between the use of CellCept® and the onset of PML. However, based • Psychiatric adverse experiences (psy- on the temporal relationship observed in chosis, mania, delusion, hallucinations, some cases, the contributory role of suicidal ideation and aggression) have CellCept® cannot be excluded. been reported in patients treated with modafinil. If psychiatric symptoms Leukoencephalopathy (PML) is a rare, occur, modafinil should be discontinued progressive, demyelinating disease of the and not restarted. central nervous system (CNS) that usually leads to death or severe disability. Caution should be exercised when PML is caused by the reactivation of the administering modafinil to patients with JC virus, a polyomavirus that resides in a history of psychosis, depression or latent form in 70 – 90% of the adult mania given the possible emergence or population worldwide. JC virus usually exacerbation of psychiatric symptoms. remains latent, typically only causing PML in immunocompromised patients. The Modafinil is not approved for use in factors leading to activation of the latent children for any indication. infection are not fully understood although abnormalities in T-cells have been Modafinil is indicated for the symptomatic described as important for reactivation of relief of excessive sleepiness associated JC virus and PML. Patients usually with narcolepsy, Obstructive Sleep present with focal CNS abnormalities and Apnoea/Hypopnoea Syndrome (OSAHS) radiographic evidence of white matter or moderate to severe chronic Shift Work disease without mass effect. Sleep Disorder (SWSD) in adult patients.

Reference: Communication from Roche, Reference: Communication from Cephalon P212828, 18th February 2008 at http:// dated 14/02/2008 at http://www.mhra.gov.uk www.mhra.gov.uk product information available on the electronic medicines compendium site http://emc. Modafinil: serious rash and medicines.org.uk psychiatric symptoms Moxifloxacin: serious hepatic United Kingdom —The manufacturer of modafinil (Provigil®) has informed physi- and skin reactions cians of new warnings and safety infor- United Kingdom/European Union — In mation regarding: agreement with EU regulatory authorities, including the Medicines and Healthcare • Serious skin rash and psychiatric Products Regulatory Agency (MHRA), the symptoms. The safety concern involves manufacturer of moxifloxacin (Avelox®) serious skin rashes requiring hospitali- has released important safety informa- zation and discontinuation of treatment tion. A recent assessment of adverse in adults and children occurring within 1 reactions associated with the use of to 5 weeks after treatment initiation moxifloxacin resulted in the following [isolated cases have been reported after information and recommendations: prolonged treatment (e.g. 3 months)].

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• Treatment with moxifloxacin is associ- information for moxifloxacin across the ated with a risk of developing fulminant European Union. hepatitis potentially leading to life threatening liver failure and risk of Reference: Communication from Bayer potentially life threatening bullous skin Schering Pharma, Bayer plc February 2008, at reactions like Stevens-Johnson-Syn- Medicines and Healthcare products Regula- drome (SJS) or toxic epidermal necroly- tory Agency (MHRA) http://www.mhra.gov.uk sis (TEN). Rimonabant: depression; • Due to limited clinical data, moxifloxacin psychiatric reactions is contraindicated in patients with impaired liver function (Child Pugh C) United Kingdom — Rimonabant and in patients with transaminases (Acomplia®) is contraindicated in patients increased > 5 fold the upper limit of with ongoing major depression or those normal. taking antidepressants. Prescribers are encouraged to take a detailed history • Patients should be advised to stop from patients before prescribing. How- treatment and to contact their physician ever, depressive reactions may occur in if early signs and symptoms of these patients who have no obvious risk factors, reactions occur. apart from obesity itself. Liver injuries possibly related to moxifloxacin were more frequently of choles- Up to the end of January 2008, 673 ADR tatic or mixed hepatocellular-cholestatic reports (reporting 1971 individual type than of hepatocellular type. Eight reactions) had been received with reports of fatal hepatic injuries were rimonabant in the UK, 423 of which were considered as possibly related to moxi- serious. Four reports had a fatal outcome. floxacin therapy. Cases of positive re- The most common reported ADRs, which challenge gave further evidence of a are labelled in the Summary of causal relationship. However, the majority Product Characteristics, were: of patients experiencing serious liver injuries where the outcome was reported • Psychiatric disorders (depression, improved or recovered. anxiety, nervousness, irritability, sleep disorders, parasomnias) TEN was reported in several cases where • Nervous-system disorders (memory a causal relationship was considered loss, dizziness, hypoaesthesia, paraes- possible; this included two cases with thesia) fatal outcome. Additionally, a total of 35 individual cases of SJS were reported, • Gastrointestinal disorders (nausea, including three cases where there was a diarrhoea, vomiting) fatal outcome and seven cases which were considered life-threatening. In these • General disorders (fatigue, asthenia) 10 cases of severe SJS, a progression to • Skin and subcutaneous disorders TEN was documented in three patients. (pruritus, sweating) Based on the large patient exposure, the incidence of both life threatening liver 876 psychiatric reactions were reported injuries and TEN is very low, although a (44% of all 1971 reported reactions). definite frequency cannot be calculated The most common psychiatric reactions from these reports. were depression and related disorders As a consequence of this review, the of mood and associated symptoms. 52 manufacturer has revised the product reactions involved suicidal and

93 Safety and Efficacy Issues WHO Drug Information Vol 22, No. 2, 2008 self-harming thoughts or behaviours, Zanamivir: neuropsychiatric most of which were suicidal ideations events (42 reports). United Kingdom — The manufacturer of Many patients who receive rimonabant zanamivir (Relenza®) Inhalation Powder are diabetic. There have been seven has updated the package insert as a reports of hypoglycaemia/decreased result of postmarketing reports (mostly blood glucose. This type of reaction may from Japan) of delirium and abnormal be due to inadequate monitoring of blood- behaviour leading to injury in patients with glucose control in patients who influenza who were receiving neuramini- have managed to reduce calorie intake dase inhibitors, including zanamivir . without appropriate adjustment of oral antidiabetics (and possibly insulin). Therefore, patients should be observed for signs of unusual behaviour and a Reference: Drug Safety Update. Volume 1, healthcare professional should be con- Issue 10, May 2008 tacted immediately if the patient shows any signs of unusual behaviour. Exenatide: risk of acute pancreatitis Zanamivir is indicated for treatment of uncomplicated acute illness due to United Kingdom — Exenatide (Byetta®), influenza A and B virus in adults and the first-in-class incretin mimetic, is a paediatric patients 7 years of age and glucagon-like-peptide-1 analogue that older who have been symptomatic for no stimulates insulin release from pancreatic more than 2 days. cells in a glucose dependent manner. Exenatide is indicated for treatment of Reference: Communication from GSK at type 2 diabetes mellitus in combination www.gsk.com posted at http://www.fda.gov/ with metformin, with or without medwatch sulphonylureas in patients who have not achieved adequate glycaemic control on Inosine ponophosphate maximally tolerated doses of these oral dehydrogenase inhibitors: therapies. Exenatide was first marketed in congenital anomalies the European Union in November 2006. United States of America —The Food Several reports of acute pancreatitis have and Drug Administration (FDA) is aware been received in association with of reports of infants born with serious exenatide use worldwide. Up to 30 congenital anomalies, including microtia September 2007, 89 reports of pancreati- and cleft lip and palate, following expo- tis had been received: 87 from the USA sure to mycophenolate mofetil (MMF) and two from Germany. One case had a during pregnancy. MMF, the active drug fatal outcome. A UK report of acute and substance in CellCept®, is an ester of the chronic pancreatitis was received in active metabolite mycophenolic acid November 2007. (MPA), the active drug substance in Myfortic®. In most cases, the mothers If pancreatitis is suspected, exenatide were taking MMF following an organ and other potentially suspect transplant to prevent organ rejection. medicines should be discontinued. However, some mothers taking MMF were being treated for immune-mediated Reference: Drug Safety Update. Volume 1, conditions such as systemic lupus ery- Issue 10, May 2008

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thematosus (SLE) and erythema multi- number of reports of drug rash with forme. Treatment began before their eosinophilia and systemic symptoms pregnancies and continued into the first (DRESS) associated with the use of trimester or until the pregnancy was Protos®. DRESS is a rare but serious detected. MMF is approved in the US for and life-threatening type of allergic use in the prophylaxis of organ rejection reaction to a drug. The condition starts in patients receiving allogeneic renal, with a skin rash, accompanied by a fever, cardiac or hepatic transplants and MPA is swollen glands, eosinophilia, adenopathy approved in the US for use in the prophy- and systemic involvement which may laxis of organ rejection in patients receiv- include hepatic, renal and pulmonary ing allogeneic renal transplants. In impairment. In most cases, the symptoms patients who are transplant recipients, resolved upon discontinuation of Protos® these drugs are almost always used in and with the initiation of corticosteroid combination with other immunosuppres- therapy. However, it has been reported sant drugs. that recovery can be slow and there is a risk of symptoms returning during the MMF and MPA increase the risk of recovery period. spontaneous abortion in the first trimester and can cause congenital malformations As of November 2007, 16 cases of in the offspring of women who are treated DRESS were reported to the CHMP. In during pregnancy. The labelling for both light of these reports , the CHMP con- MMF and MPA was revised in November cluded that the use of Protos® is linked to 2007 to change the Pregnancy Category an increased risk of DRESS and recom- to “D” (positive evidence of human fetal mended that warnings on severe hyper- risk, but potential benefits may warrant sensitivity syndromes, including DRESS use of the drug in pregnant women and Stevens Johnson syndrome be despite the potential risk) and to add included in the product and patient these findings about the risk of early information pregnancy loss and congenital malformations to the boxed warning. To date, the Health Sciences Agency Reference: FDA Alert, 16 May 2008 at (HSA) has not received any ADR reports http://www.fda.gov/medwatch associated with Protos® and DRESS. There is one case of a patient who developed Stevens Johnson syndrome Strontium ranelate : life- after taking both Protos® and Arcoxia® threatening allergic reactions (etoricoxib) simultaneously for about one Singapore — Strontium ranelate month. (Protos®, Servier) has been registered since July 2006 for the treatment of post- In view of this emerging safety concern, menopausal osteoporosis to reduce the prescribers are reminded to alert their risk of vertebral and hip fractures. Since patients of the risk of severe allergic its launch in Europe in 2004, Protos® has reactions and to inform them to stop been registered in 64 countries and has a Protos® immediately should a rash occur total of about 570 000 patient-years of and to seek medical advice. For patients exposure. who have stopped treatment due to hypersensitivity reactions, Protos® In November 2007, the European Medi- should not be re-introduced. cines Agency’s (EMEA) Committee for Medicinal Products for Human Use Reference: Strontium (Protos®) - A safety update. 25 Mar 2008: at http://www.hsa.sg (CHMP) was alerted to an increasing

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Lapatinib and hepatoxicity Telbivudine and peripheral Singapore — In consultation with HSA, neuropathy the manufacturer of lapatinib (Tykerb®) Singapore — Telbivudine (Sebivo®) is has informed healthcare professionals of indicated for the treatment of HBeAg- new safety information on hepatotoxicity. positive and HBeAg-negative chronic hepatitis B in patients who have compen- From the manufacturer’s worldwide sated liver disease, evidence of viral safety database, 39 cases of hepatotoxic- replication and active liver inflammation, ity were identified, of which 38.5% of and who are nucleoside analogue naive. subjects were receiving lapatinib monotherapy while 53.8% were receiving In a pilot clinical trial, 8 cases of periph- lapatinib in combination with other eral neuropathy were reported out of the chemotherapies, such as capecitabine. 48 patients treated with telbivudine and a standard dose of pegylated interferon Majority of the key cases were from alfa-2a. The time to onset for the event clinical trials, which yielded a crude was approximately 2 to 6 months. In incidence of 0.4% for hepatobiliary events contrast, the rate of peripheral neuropa- in the entire lapatinib clinical program thy in the 2-year pivotal study with telbivu- while 7 cases of hepatotoxicity were from dine monotherapy was uncommon. spontaneous sources. There have been 13 incidences of death with reported liver- As the risk of developing peripheral related events. neuropathy appears to be increased in the telbivudine and pegylated-interferon Healthcare professionals are advised to alfa-2a combination, the manufacturer is monitor their patients’ liver functions working with the Health Sciences Agency before initiating treatment and at approxi- (HSA) to update the product information. mately monthly intervals thereafter or as clinically indicated. Tykerb® should be Reference: Peripheral neuropathy seen with discontinued and not restarted in patients the combination treatment of Sebivo® (telbivu- with severe changes in liver function. dine) with pegylated interferon alfa-2a, 17 March 2008 at http://www.hsa.sg Reference: Tykerb® (lapatinib) and new safety information on hepatotoxicity, 1 April 2008 at http://www.hsa.sg

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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International Nonproprietary Names for monoclonal antibodies: IFPMA proposal

This summary represents the IFPMA proposal presented to the 46th Consultation on International Nonproprietary Names (INNs) for Pharmaceutical Substances held at the World Health Organization in Geneva in April 2008. The proposal was developed by the IFPMA (International Federation of Pharmaceutical Manufacturers & Associa- tions) Biotech Working Group, which includes twenty companies, two regional and three national associations located in Europe, Japan and USA. The pioneering work of Kohler and Milstein (1) in the 1970s provided the means to produce monoclonal antibodies (MAbs) derived from a single clone of cells which bind to a single antigenic determinant with predefined specificity. This paved the way to use this class of biomolecules as diagnostic tools as well as therapeutic drug substances for treatment of cancer, auto-immune, and other diseases. Technological advances in the generation of antibodies with reduced immunogenicity permitted the development of MAb-based therapies as a major strategy in biomedicine (2). Today, more than 20 MAb-based medicines have been approved for marketing, and a further 160 MAbs were in development in 2006 (3). The appearance of the first MAb-based drugs in the late 1980s created the impetus for the WHO INN programme to establish a naming system for monoclonal antibodies in 1990/91. By 2006, more than 140 INNs had been selected for MAbs. The system was gradually expanded but the general policy for naming of MAbs remained unchanged [reviewed in (4)]. The nomenclature rules for monoclonal antibodies are complex. Furthermore, current developments in the use of different antibody types with different functions, antibody fragments and antibody glycoengineering add to this complexity. Therefore, it was decided (5) that consideration should be given to establishing a small expert group to review these developments and to make specific recommendations on INN policy for monoclonal antibodies. In order to support this process, the IFPMA has developed Proposals for principles for INNs of new monoclonal antibodies (6). This summary is intended to give a short overview on MAbs, their molecular structure and aspects relevant to their use as pharmaceutical drug substances, and to communicate and explain the IFPMA naming proposal. It should be emphasized that the additional explanations given in this paper do not necessarily represent a harmonized IFPMA position but reflect the per- sonal views of the authors.*

* The article was prepared by Anna-Maija Autere, Nicole Wagner and Georg-Burkhard Kresse from Roche on behalf of International Federation of Pharmaceutical Manufacturers & Associa- tions (IFPMA) Biotech Working Group: http://www.ifpma.org/Issues/Biologicals/. Correspond- ence: Ryoko Krause, IFPMA at [email protected]

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Molecular structure of antibodies – binding fragments comprising one light the immunoglobulin molecule chain and the VH and CH1 parts of one heavy chain), responsible for antigen Antibodies, also called immunoglobulins, specificity and binding, and F (“fragment are a large group of closely related glyco- c crystallizable”, comprising the CH2 and proteins with a molecular weight of up to C 3 parts of two heavy chains). 150 kDa. Each immunoglobulin molecule H is composed of two identical heavy Based on the amino acid sequence dif- chains and two identical light chains, ferences in the constant part of the heavy linked together by disulfide bonds (Fig.1). chains, immunoglobulins are classed by The amino acid sequences of the amino- isotypes (e.g. human IgA, IgG, IgM, IgD, and IgE). All licensed therapeutic antibod- terminal regions, referred to as VH and VL, are highly variable and are involved in ies belong to the IgG isotype. Human antigen binding. The constant part of the IgG–Fc contains carbohydrate residues bound to residue Asn297 in each of the light chain is called CL, and the constant part of the heavy chain is sub-divided into CH2 domains, thus characterizing IgG as a glycoprotein. In addition, 15–20% of three domains CH1, CH2, and CH3. Two heavy and two light chains form a “Y- human IgG molecules have N-linked shaped” hetero-tetrameric superstructure. oligosaccharides within the Fab region (7). It consists of three structurally independ- The oligosaccharides provide important ent moieties connected by a flexible hinge recognition sites mediating a variety of region, which are termed F (the antigen- interactions (see 8) and play specific ab structural roles.

Figure 1. Structure of an IgG Molecule

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Within the IgG isotype, there are four thereby increases in-vitro ADCC more different sub-classes (IgG1, IgG2, IgG3, than 50-fold. The presence or absence of and IgG4) differing in their amino acid galactose and sialic acid residues also sequence, hinge length, binding to Fc influences ADCC (12) and CDC. receptors and complement, and biological function. In development of therapeutic Several studies (e.g. 13,14) have high- monoclonal antibodies, scientists have lighted the importance of FcgR-mediated killing of target cells for the efficacy of focused on the IgG1, IgG2, and IgG4 subclasses (9). antibody treatment in cancer therapies, which represents an essential mechanism Immune effector functions and for efficacy. Modulation of IgG glycoengineering glycosylation (“glycoengineering”) which results in removal of part or all of the Antibodies specifically bind to their fucose residues in order to enhance antigens via their F fragment regions. In ab potency is considered a promising tech- general, they thereby can prevent patho- nology to enhance the efficacy of thera- gens from entering or damaging cells, peutic MAbs (15), as already demon- interfere with signal transduction medi- strated in murine xenograft models (16). ated by interactions of ligands with cell MAb-based medicines containing surface receptors, and induce cell-death glycoengineered antibodies have entered mechanisms through apoptosis or by clinical development. blocking the action of survival pathways.

In contrast to the importance of Fc inter- Furthermore, by virtue of interaction sites actions in cancer, in some disease areas located in the Fc part of IgG, antibodies (e.g. for treatment of inflammatory dis- can also stimulate removal of a pathogen eases) Fc-mediated effects can lead to or tumour cell by macrophages and other safety issues and it may be desirable to cells of the immune system. This is minimize or even eliminate Fc-mediated mediated by interaction with Fc-gamma interactions. Thus, glycosylation of receptors (FcgRs) present on the immune antibodies can be crucial for their clinical cells and eliciting antibody-dependent profile, including aspects of safety and cellular cytotoxicity (ADCC). Antibodies efficacy, and the consistency of glyco- can also trigger direct pathogen or cell sylation has to be carefully controlled. destruction by stimulating other immune responses such as the complement Monoclonal antibody production pathway (complement-dependent cyto- and heterogeneity toxicity, CDC). These effects have been According to the original Kohler-Milstein termed “immune effector functions” of technology, monoclonal antibodies are antibodies. obtained from hybridoma cells. Today, therapeutic MAbs are usually produced It has been shown (10,11) that the pres- using recombinant DNA technology. Due ence and structure of the Fc-bound to the requirement for glycosylation, all carbohydrate moieties of the IgG mol- antibody therapeutics that are currently ecule are essential for binding to a certain licensed are manufactured from mamma- subtype of FcgRs (FcgRIIIa) and promo- lian cell culture, using e.g. Chinese tion of effector functions: IgG molecules hamster ovary (CHO) and mouse mye- with an ungycosylated Fc portion retain loma (NS0 or Sp2/0) cells. Other systems little ability in activating complement and based on transgenic animals, yeast, binding to FcgRs. On the other hand, the plants, etc. are under development. lack of a fucose residue in human IgG1 Unglycosylated Fab fragments can be enhances the binding to FcgRIIIa and produced from prokaryotic systems.

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Manufacturing of recombinant MAbs, Lowering the immunogenicity which is a complex multi-step process, Monoclonal antibodies obtained by the requires the same high standards in original Kohler-Milstein procedure, and process development, validation and the first MAb which was licensed in 1986 control as for other recombinant thera- for use in therapy (muromonab-CD3), peutic proteins. Sound product and were murine proteins. However, rodent process knowledge (preferentially based MAbs can elicit an immunogenic re- on “quality by design” concepts) is indis- sponse referred to as human anti-mouse pensable in order to ensure and maintain antibodies (HAMA). Furthermore, thera- product quality. The safety and efficacy of peutic efficacy may be reduced by rela- antibody therapeutics, including their tively faster clearance (as compared to stability and immunogenic potential, are human antibodies) and weak effector critically dependent on post-translational functions in humans (19). Therefore, modifications such as, but not limited to, efforts were made to make MAbs more glycosylation which are highly depending “human-like” by genetically fusing rodent on the manufacturing and control charac- variable domains to human constant teristics of the process. domains (resulting in “chimeric” antibodies which still contain about 35% rodent In this context, it should be emphasized sequences). “Humanized” antibodies with that even highly purified recombinant only approximately 10% rodent se- proteins, due to the complexity of both quences have also been produced by their molecular structure and their manu- grafting only the six loops, termed facturing process, are never single and complementarity determining regions uniform molecular entities, but families of (CDRs), of the antibody sequence which closely related molecular variants (18,19). can potentially interact with the target These variations will be introduced by the molecule to a human antibody framework, manufacturing cell itself, as well as by the combined with some additional sequence production process. For an IgG antibody, optimization. These chimeric or human- it has been estimated that, even consider- ized antibodies indeed exhibit less ing only a limited number of glycoform immunogenicity, and most of the mono- variants (17), up to 108 variants are clonal antibody products presently li- theoretically possible; in fact, variability censed contain either chimeric or human- may be even greater since there may be ized antibodies. many more glycoforms than considered in this analysis (7). In contrast to the situa- More recently, methods have become tion with small, chemically synthesized available to obtain MAbs with “fully molecules, current protein-analytical human” sequence (20), either by using methods are not able to characterize phage display selection techniques, or by complex proteins completely, and the generating the antibodies in mice trans- functional impact is known only for genic for the human immunoglobulin particular attributes (or defined combina- genes. Currently, two therapeutic “fully tions of some attributes). Therefore, for human” MAbs (adalimumab, panitumu- recombinant proteins including mono- mab) are licensed, with many more being clonal antibodies manufactured by in clinical development. Alternatively, different, independently developed efforts are ongoing to reduce the immu- processes, differences in microhetero- nogenicity of chimeric MAbs by “de- geneity have to be expected whose immunization” based on in-silico identifi- impact on clinically relevant properties cation of potential linear T-cell epitopes usually cannot be predicted. which then are removed by altering the sequence. Several of these MAbs which

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strictly cannot be designated as “chi- oligomeric conjugates. Several Fab frag- meric” nor “humanized” or “human” have ments have already been licensed for use entered clinical development. as drugs (e.g., abxicimab, ranibizumab, 99mTc-sulesomab). As a result of their However, even “fully human” MAbs have smaller size, antibody fragments usually a significant immunogenic potential in exhibit shorter in-vivo half-life than intact patients. The formation of antibodies may antibodies. However, their in-vivo half life be due to the presence of foreign se- can be increased by conjugation with quences or epitopes, but also to product poly(ethylene glycol)(PEG). quality issues (e.g., presence of aggre- gates) and/or patient- and disease-related Due to their exquisite antigen binding factors. Thus, even small differences in specificity, antibodies (or their Fab frag- therapeutic protein products may lead to ments) can be used for targeting cytotoxic unexpected immunogenicity. drugs, cytokines, toxins, or radio-isotopes to the desired location, e.g. tumour cells Bi-specific antibodies, antibody (22). Licensed products following this fragments, antibody conjugates principle include e.g. ibritumomab tiux- Whereas unmodified, intact antibodies etan, gemtuzumab ozogamicin, or represented the first wave of licensed (131I)tositumomab. immunotherapeutic reagents, it soon became clear that it is often desirable to The Fc part of the IgG molecule, when improve clinically relevant properties, fused genetically to otherwise short-lived such as pharmacokinetics, potency, protein sequences, can serve to extend avidity, or half-life. Among the approaches the in-vivo half-life considerably. Several to address these topics is the construc- fusion proteins relying on this concept tion of bi-specific antibodies (containing have been licensed (e.g., etanercept, two different binding specificities con- rilonacept, alefacept). nected together) which in some cases are even designated as “trifunctional” due The present policy of MAb naming to immune effector functions mediated by International Nonproprietary Names (INNs) are unique names which are the Fc part (e.g. catumaxomab). globally recognized. They are assigned to allow the clear and unambiguous identifi- It is possible to minimize Fc-mediated effects in therapeutic MAbs by selecting cation, safe prescription and dispensing IgG subclasses with low effector func- of active pharmaceutical ingredients based on molecular characteristics and tions, such as IgG2, IgG4, or IgG1 mu- tants. Another option to eliminate un- pharmacological class (23). Since initiation of the INN system in 1950, INNs wanted Fc functionalities is the use of antibody fragments obtained by proteoly- have become essential for health profes- sis of intact antibodies or by recombinant sionals as a tool for correct prescription expression of monovalent fragments and are used by drug manufacturers, regulatory authorities, authorities involved (such as Fab, Fv, or single-chain Fv frag- in reimbursement and some other inter- ments) which are devoid of the Fc part of the IgG molecule (21). Due to their ested parties. They play a key role in smaller size, these antibody fragments communication, prescription, interchange- may exhibit better pharmakokinetics for ability and reimbursement of medicines tissue (e.g., tumour) penetration. If multi- as well as pharmacovigilance. valent binding is desired to increase retention times on the target, such frag- The concept of INNs was initially devel- ments can be engineered into di- or oped for small chemical entities that can

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be fully characterized by physicochemical prietary Names (INNs) for Pharmaceutical means. Due to the progress in biomedical Substances held at WHO Headquarters and biotechnological research, medicinal on 22–24 May 2007 (5) that consideration products containing significantly more should be given to review these develop- complex substances of biological origin ments and to make specific recommenda- have been and will continue to be devel- tions on a revised INN policy for mono- oped. As a consequence, INNs need to clonal antibodies. be assigned for these complex products. The challenge is that these active phar- IFPMA proposals for principles maceutical ingredients (APIs) are often on INNs for new MAbs very large macromolecules which cannot With the intention of supporting this be fully characterized analytically. More- process, IFPMA has developed the over, these APIs are not single specific following ideas for principles which, from ingredients but mixtures of molecular the industry view, should preferably be species which are differently glyco- followed in the naming of new MAbs (6). sylated, or otherwise modified post- The following proposals should serve to translationally. focus attention on a number of important A systematic scheme for INNs of MAbs aspects. Proposals approved by the was implemented in the early 1990s. The IFPMA Biotech Working Group are printed in bold italic. common stem is ‘-mab’, sub-stems indicate the source of the product (e.g. -o- for mouse, -u- for human, -xi- for chi- 1. The naming convention for monoclonal antibodies should follow the meric, -zu- for humanized), and further sub-stems indicate the disease or target same policy as established for all class (e.g. -li- for immunomodulators, - (glyco)proteins. Thus, protein drug vi(r)- for viral) or tumour type (e.g. -co- for substances (including MAbs) with differences in amino acid sequence colon, -ma(r)- for mammary, -me(l)- for melanoma, -tu(m)- for miscellaneous). should always have different INNs. The prefix is chosen randomly, but should Monoclonal antibodies are glycoproteins, contribute to a euphonious and distinctive name. If necessary, a second word is and there is good reason to use the same added, indicating radiolabelling or conju- general policy as for naming of other glycosylated proteins where the INN gations, e.g. to toxins. In this case, the infix -toxa- can be inserted. Several system is well established and proved to further rules and restrictions apply (i.e., be useful for all stakeholders. avoid conflicts with trademarks and brand names). To accommodate new technical 2. IFPMA proposes to continue the use developments the system has become of the common stem –mab for monoclonal antibodies. For antibody frag- increasingly complex. Due to the increas- ments (such as F fragments), the use ing number of INNs selected for MAbs, ab difficulties have arisen especially in those of –fab instead of –mab might be considered. MAb groups which attract the biggest research interest, e.g. cancer and autoimmune diseases. As a conse- We propose to differentiate between complete (intact) antibodies and antibody quence, new INNs tend to become longer, more complicated, and there is fragments which presently are also the potential for confusion. named using the same stem –mab (e.g., abxicimab, ranibizumab). Differentiation Therefore, it was decided at the 44th would be helpful for the INN users. Consultation on International Nonpro- However, it is open for discussion

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whether other distinct stems should be using designators (e.g., Greek letters, defined for products based on other details to be decided by WHO) as for immunoglobulin fragments such as Fv, other glycosylated proteins. This require- scFv, or other fragments (see 21), or ment is justified scientifically since it has whether a general stem (such as –fab) clearly been shown that differences in might be used to indicate that the product glycosylation (e.g., fucosylation, galacto- is derived from a Mab type structure. sylation, sialylation) influence immune effector functions and thus may have an 3. An invented part of the INN is still impact on clinically relevant properties. considered necessary. IFPMA pro- Consequently, MAbs with an identical poses that WHO makes efforts to amino acid sequence but a different provide related names for MAbs glycosylation pattern have to be consid- directed against the same molecular ered different drug substances and target (although these MAbs neverthe- therefore should have different INNs. less may differ in amino acid sequence, epitope specificity, immune In accordance with the naming policy for effector functions, binding constants, glycosylated proteins, MAbs with a etc.). different glycosylation pattern (or other differences in post-translational modifica- The specificity of a MAb for its antigen tions) should have distinct INNs even if (which represents the molecular target) is their amino acid sequence is the same. the most important element of information This is important because cases are characterizing a monoclonal antibody as expected where MAbs with the same a drug substance. Presently, antigen amino acid sequence, but proven or specificity is not apparent from the INNs potential differences in glycosylation are selected for MAbs. Since the number of developed which may possess different clinically validated MAb targets is limited, clinical properties. Such differences may it can be expected that there will be either be intended, e.g. in glycoengineer- several MAbs entering clinical studies or ed antibodies, or unintended but inevita- obtaining marketing approval which are ble due to the use of different, independ- directed against the same antigen – in ent manufacturing processes, e.g. in fact, this is already reality (e.g., cetuxi- subsequent-entry (stand-alone follower or mab and panitumumab both adress the biosimilar) products. epidermal growth factor (EGF) receptor although this is not evident from the 5. At the time of INN application it may respective INNs). It would help the users not yet be clear whether modification of INNs if related, although different, INNs (e.g., glycosylation) is identical or would be provided for MAbs addressing different. Therefore, monoclonal the same antigen. However, it is not antibodies made independently (i.e., suggested that the INN system should by different manufacturers using develop systematic naming principles for different processes) should generally all potential antigens, which clearly is not obtain distinct INNs. These distinct possible. INNs should have the same stem but include different designators or identifiers. 4. Consistent with the naming conven- tions for other glycoproteins, it is It should be noted that this policy in mandatory that differences in post- practice will only be efficient if WHO and translational modifications (for exam- the drug regulatory authorities agree to ple, but not limited to, the make it mandatory for the second manu- glycosylation pattern) are indicated in facturers to present their substances to the INN of MAbs. This might be done WHO and apply for a distinct INN.

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Manufacturers usually apply for INNs targets) which may be involved in more during early clinical development when than one indication or disease. Therefore, the final manufacturing process may still it is likely (and already reality in some be under development and the quality cases) that MAb drug substances will be profile, including the modification (e.g. used in more than one disease (e.g., glycosylation) pattern of the product to be cancer and inflammatory diseases). While commercialized, has not yet been finally it is recognized that information on the established. So, as a matter of precau- disease is useful for the physician, IFPMA tion, distinct INNs should be given at that believes that WHO should discuss time to MAbs made by different manufac- whether it is appropriate to include turers using different, independent proc- information on the disease, or rather on esses. Even if it turns out later on that the the molecular target (e.g., CD20, HER-2, glycosylation pattern of two products is etc.) in the INN. the same, the issue of having two products with identical properties but distinct In cases where the same MAb is used in INNs can be considered minor compared therapy for more than one disease (e.g., to the risk of having two products with the rituximab in non-Hodgkin lymphoma as same INN but different clinical properties well as rheumatoid arthritis), it is confus- because in this latter case, “clear identifi- ing when the INN includes information cation, safe prescription and dispensing” relating to only one of these diseases as requested by WHO (23) based on the only. Although this can also be the case INN would be impossible. with chemically synthesized, low-molecular weight drug substances, it is more This concept does not contradict the fact likely to occur with monoclonal antibody- that there may be some batch-to-batch based medicines because biopharma- variability of the glycosylation pattern, as ceuticals discovery and development is well as slight glycosylation differences based on interfering with complex after manufacturing changes in a given signaling pathways, which may be in- product. In these cases, the range of volved in multiple diseases, rather than variability is validated by the results of solely on organ pathology. Therefore, it clinical development and by the compara- should be considered to include informa- bility exercise to be performed by the tion on the antigen/molecular target (cf. manufacturer according to the ICH Q5E proposal 3 above) rather than on the guideline (24) in case of process disease in the name. changes. Thereby it is ensured that within the design space defined by these data, 7. IFPMA does not believe that more there is no adverse impact on the quality, detailed information on the mecha- safety or efficacy of the drug product. So nism of action (e.g., inhibitory, stimu- there is no need to select a distinct INN latory, etc.) has to be part of the INN to after manufacturing changes provided avoid too much complexity of the that pre- and post-change comparability names. This information should rather be is demonstrated. part of the substance description. How- ever, this should be left to WHO’s discre- 6. Generally, the INNs contain information. tion on the “pharmacological class” of the substance. Until now, this has 8. Specific information for which subtype been done for MAbs by including a of disease (e.g., kind of tumour) an sub-stem for the “disease or target” antibody drug substance is used (e.g., class. However, targeted therapies such colon, testis, ovary, etc.) is not useful as monoclonal antibodies often address because many MAbs in oncology may be biological mechanisms (and molecular used for several tumour types. Naming

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according to the first indication (which other pegylated proteins, pegylated MAbs often will turn out not to be the most and Fabs should obtain the prefix “peg-”. important) would be misleading. IFPMA Differences in conjugation (e.g., site of proposes to remove this information from modification, conjugate chemistry, linker the INN. chemistry, chain length of polymer, etc.) would require differentiation as for other 9. In order to simplify the INNs for types of modification. As far as possible, MAbs, IFPMA also considers INN the naming of antibody conjugates should differentiation dependent on the follow the naming convention applied to “source of product” (human, mouse, non-antibody conjugates. chimeric, humanized, etc.) no longer necessary. This distinction is scientifi- 11. Fusion constructs containing parts cally questionable due to the fact that of an immunoglobulin molecule ge- there are emerging approaches to design netically fused to another sequence MAb sequences in silico, in order to have to be treated as a new protein reduce immunogenicity, for removal of T- and should obtain individual INNs. cell epitopes. The resulting MAbs can WHO should discuss whether it is more neither be classified “murine” or appropriate to follow the policy for MAb “chimerized”, “humanized”, or “human”. naming, or for non-antibody proteins in The same principle applies to MAbs these cases. generated by, for example, phage display. This type of information should be part of In the present INN policy (4), fusion the description of the substance rather constructs containing the immunoglobulin than the INN. Fc part connected to a receptor molecule (or part of a receptor molecule) have Proposals 8 and 9 are intended to sup- been designated with the stem –cept port simplification of the MAb INNs. This (e.g., alefacept, abatacept, rilonacept). can only be done if some of the above From these names, it is not apparent that mentioned informative parts — which the products contain part of an immu- according to the present policy are noglobulin sequence. In future, there may included in the names — will be removed. be fusion products which contain e.g. Fc Information on the “kind of tumour” as sequences fused to other peptide (but not well as on the “source of product” both necessarily receptor) sequences. While it are scientifically questionable and can is evident that each of these products will even be misleading for the user, and need a distinct INN, it is proposed to therefore need not necessarily be part of consider whether the presence of anti- the name itself. However since this body (Fc) sequences should be indicated information certainly is helpful in some in the INN. situations, it should be retrievable within the substance description which is Conclusion associated with the INN. Due to technological progress and the increasing number of MAb-based drugs 10. Distinct names should be assigned under development and on the market, a to derivatives of antibodies including revision of the present policy for INNs of e.g. bispecific antibodies, antibody- MAbs should be performed. With the peptide or antibody-toxin conjugates, proposals described in this paper, IFPMA and radio-labelled antibodies. INNs for would like to support this process and conjugates might be composed (e.g. as contribute to the establishment of a MAb two separate words) from the names naming system that is able to accommo- assigned to the individual components. In date the recent and emerging technical accordance with the naming policy for developments in the field of monoclonal

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antibodies, while at the same time being 10. Tao, M.H., Morrison, S.L. Studies of as clear and simple as possible. aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and References effector functions mediated by the human IgG constant region. J. Immunol. 1989; 143:2595– 1. Kohler, G., Milstein, C. Continuous cultures 2601. of fused cells secreting antibody of predefined 11. Mimura, M., Sondermann, P., Ghirlando, specificity. Nature 1975; 256:495–497. R., Lund, J., Young, S.P., Goodall, M., Jefferis, R. Role of oligosaccharide residues of IgG1- 2. Brekke, O.H., Sandlie, I. Therapeutic Fc in FcgRIIb binding. J. Biol. Chem. 2001; antibodies for human diseases at the dawn of 276:45539-45547. the twenty-first century. Nature Revs. Drug Discovery 2003; 2:52–62. 12. Scallon, B.J., Tam, S.H., McCarthy, S., Cai, A.N., Raju, T.S. Higher levels of sialylated 3. PhRMA (Pharmaceuticals Research and Fc glycans in immunoglobulin G molecules Manufacturers of America). Medicines in can adversely impact functionality. Mol. development: Biotechnology. 2006. http:// Immunol. 2007; 44:1524–1534. www.phrma.org/files/Biotech%202006.pdf. 13. Cartron, G., Dacheux, L., Salles, G., Solal- 4. WHO Programme on International Nonpro- Celigny, P., Bardos, P., Colombat, P., Watier, prietary Names. International Nonproprietary H. Therapeutic activity of humanized anti- Names (INN) for biological and biotechnologi- CD20 monoclonal antibody and polymorphism cal substances (a review). INN Working in IgG Fc receptor FcgRIIIa gene. Blood 2002; Document 05.179. 2007. 99:754–758. 14. Clynes, R.A., Towers, T.L., Presta, L.G., 5. WHO Programme on International Nonpro- Ravetch, J.V. Inhibitory Fc receptors modulate prietary Names. 44th Consultation on Interna- in vivo cytotoxicity against tumor targets. tional Nonproprietary Names (INNs) for Nature Med. 2000; 6:443–446. Pharmaceutical Substances, Executive Summary. 2007. http://www.who.int/medi- 15. Umana, P., Jean-Mairet, J., Moudry, R., cines/services/inn/FinalConsolidated Amstutz, H., Bailey, J. Engineered glycoforms ExecSum44INN.pdf [cited 2008 Apr 24]. of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxicity. 6. IFPMA. Proposal to the WHO INN Expert Nature Biotechnol. 1999; 17:176–180. Group: Principles for naming of new monoclonal antibodies. 2008. http://www.ifpma.org/ 16. Friess, T., Gerdes, C., Nopora, A., Patre, fileadmin/templates/ifpmaissues/pdfs/ M., Preiss, S., van Puijenbroek, E., Schuell, 2008_03_21_IFPMA_Proposal_for_naming_of_ C., Bauer, S., Umana, P., Klein, C. GA101, a new_monoclonals.pdf [cited 2008 Apr 24]. novel humanized type II CD20 antibody with glycoengineered Fc and enhanced cell death 7. Jefferis, R. Glycosylation of recombinant induction, mediates superior efficacy in a antibody therapeutics. Biotechnol. Prog. 2005; variety of NHL xenograft models in compari- 21:11–16. son to rituximab. Blood. 2007; 110:2338. 8. Arnold, J.N., Wormald, M.R., Sim, R.B., 17. Kozlowski, S., Swann, P. Current and Rudd, P.M., Dwek, R.A. The impact of future issues in the manufacturing and glycosylation of the biological function and development of monoclonal antibodies. Adv. structure of human immunoglobulins. Annu. Drug Delivery Revs. 2006; 58:707–722. Revs. Immunol. 2007; 25:21–50. 18. ICH Q6B Guideline: Specifications: test 9. Salfeld, J.G. Isotype selection in antibody procedures and acceptance criteria for engineering. Nature Biotechnol. 2007; biotechnological products, 1999, http:// 25:1369–1372. www.ich.org/LOB/media/MEDIA432.pdf [cited 2008 Apr 16].

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19. Walsh, G., Jefferis, R. Post-translational 22. Schrama, D., Reisfeld, R.A., Becker, J.C. modifications in the context of therapeutic Antibody targeted drugs as cancer therapeu- proteins. Nature Biotechnol. 2006; 24:1241- tics. Nature Revs. Oncology 2006; 5:147-159. 1252. 23. World Health Organization. Guidelines on 20. Presta, L.G. Engineering of therapeutic the use of International Nonproprietary Names antibodies to minimize immunogenicity and (INNs) for pharmaceutical substances, WHO/ optimize function. Adv. Drug Delivery Revs. PHARM S/NOM 1570, 1997. 2006; 58:640-646. 24. ICH Q5E Guideline: Comparability of biotechnological/biological products subject to 21. Hudson, P.J., Souriau, C. Engineered changes in their manufacturing rocess, 2005, antibodies. Nature Med. 2003; 9:129-134. http://www.ich.org/LOB/media/MEDIA1196.pdf [cited 2008 Apr 24].

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Regulatory Action and News

Dydrogesterone withdrawn mg daily for up to five days). Lumiracoxib for commercial reasons was not widely used in Australia until it was included on the Pharmaceutical United Kingdom — Dydrogesterone Benefits Schedule (PBS) in July 2006. (Duphaston ®) is to be withdrawn from the market from March 2008 for commer- Following the evaluation of trial data cial reasons. Dydrogesterone was li- showing that the efficacy of a 100 mg censed for use in several indications, daily dose was comparable to that of the including threatened or recurrent miscar- 200 mg dose, a 100 mg tablet was riage, dysfunctional uterine bleeding, and registered for use in Australia in June hormone replacement therapy. 2007 for the relief of symptoms of osteoarthritis. In the 12 month period up to the A Public Assessment Report has re- end of July 2007, 567,903 prescriptions viewed evidence for the efficacy of for lumiracoxib were dispensed in Aus- progesterone and dydrogesterone in the tralia. maintenance of pregnancy in women with threatened miscarriage or recurrent In March 2007, the first Australian report miscarriage. of serious hepatotoxicity associated with the use of lumiracoxib was received. For several decades, progesterone and Concerns about this case stimulated a progestogens (such as dydrogesterone) priority review of the general safety profile have been used to maintain early preg- of lumiracoxib, with a focus on hepato- nancy. However, this practice seems to toxicity. have been based on theoretical consid- erations rather than robust evidence of By the time of the Australian Adverse efficacy. Although the methodological and Reactions Advisory Committee (ADRAC) ethical difficulties associated with con- meeting on 10 August, the Therapeutic ducting efficacy trials in these indications Goods Administration (TGA) had received need to be considered, the quality of eight reports of serious liver injury associ- much of the evidence is generally poor ated with the use of lumiracoxib. There relative to today’s standards. were also three reports of minor increases in liver enzymes. There were five Reference: Medicines and Healthcare reports of hepatic failure, including two products Regulatory Agency (MHRA) informa- fatalities and two liver transplants, and an tion release. http://www.mhra.gov.uk/ Safetyinformation additional three reports of severe jaun- dice or acute hepatitis without liver failure. Withdrawal of lumiracoxib ADRAC was informed of a further three Australia — Lumiracoxib is a selective overseas reports of hepatic failure with COX-2 inhibitor, which was registered in lumiracoxib, all from South America. Australia in 2004 for the symptomatic ADRAC also reviewed data provided by relief of osteoarthritis (at 200 mg daily) the sponsor of lumiracoxib regarding liver and for the treatment of acute pain and abnormalities seen in the clinical trial pain due to primary dysmenorrhoea (400 programme.

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At the August meeting, it was known that The TGA has required testing of all a 100 mg dose of lumiracoxib had been heparin containing products in Australia registered recently in Australia. However, since March 2008, following the identifica- the Committee was concerned there was tion of a contaminant known as "over- insufficient evidence for an adequate sulphated chondroitin sulphate (OSCS)" margin of safety with the 100 mg daily implicated in several severe allergic dose because of the possibility that the reactions in the USA and Europe. hepatotoxicity of lumiracoxib may be idiosyncratic; that lower doses may be As a result of this testing contamination hepatotoxic in specific populations such with OSCS has been detected in five as the elderly, low-weight individuals, or batches of the low molecular weight those with other underlying disease; or heparin product Clexane®. These that the 100 mg daily dose may be batches have been quarantined pending exceeded by patients seeking more pain further assessment. relief. ADRAC also considered that the apparent rate of severe liver injury with To date, there have been no reports of lumiracoxib appeared greater than for adverse events in Australia of the type other marketed nonsteroidal anti-inflam- reported in the United States associated matory drugs. with heparin products. Nevertheless, the TGA has decided to quarantine the After the above review and advice from affected batches so no patients are put at ADRAC that the risks of lumiracoxib undue risk at this time. outweighed its benefits, the TGA acted immediately to cancel the registration of Responses from regulatory agencies all forms of lumiracoxib in Australia, on around the world have varied, with some the grounds that failure to cancel the agencies initiating recalls and others registration would create an imminent risk continuing to allow contaminated product of death, serious illness or serious injury. to remain in the market, based on the Following the cancellation, the TGA view that in many clinical settings the advised that all patients should stop benefits of continued use of these blood taking lumiracoxib immediately, and thinning agents outweigh the possible should be assessed by their doctor for risks from contamination. any evidence of liver damage (see TGA website at www.tga.gov.au/alerts/ Reference: Therapeutic Goods Administration prexige.htm) Alert, 22 April 2008. http://www.tga.gov.au/ alerts/medicines/clexane.htm Extracted from Australian Adverse Drug Sweden — On 23 April 2008, the Medical Reactions Bulletin, Volume 27, Number 2, Products Agency decided to recall the April 2008 contaminated batches of enoxaparin (Klexane®) found on the Swedish market. Enoxaparin contamination: The level of contamination is low and the batches recalled recall was made as a precautionary measure. Australia —The Therapeutic Goods Administration (TGA) has recalled five During January and February 2008 batches of the anticoagulant medicine Baxter recalled almost all of their heparin enoxaparin (Clexane®) due to the detec- products from the US market after reports tion of an impurity in the affected batches. on serious adverse events. At the begin-

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ning of March 2008, the US Food and Xyntha® is licensed for the control and Drug administration (FDA) announced prevention of bleeding, which can occur that the adverse events were associated spontaneously or after an accident or with the presence of an unknown heparin- injury in patients diagnosed with like impurity that could only be detected hemophilia A. This recombinant Factor with new analytical methods presented on VIII is produced without additives from the FDA website. human or animal material, which further minimizes any risk of infection from the The Medical Products Agency decided product. that all Companies supplying heparin products for the Swedish market should In clinical trials, Xyntha® was shown to test their products for this specific con- be effective at preventing or controlling tamination. A few batches of the low bleeding, including preventing bleeding in molecular weight heparin, Klexane®, surgery, for hemophilia A patients. Gener- were found to be contaminated with low ally, the most frequently reported adverse levels of the same impurity as in the reaction was headache. Most adverse unfractionated heparin detected in the reactions reported in either study were USA, i.e. oversulphated chondroitin considered mild or moderate in severity. sulphate (OSCS). Therefore, the Medical In addition, two of 89 individuals who Products Agency decided to recall these received 50 days of treatment with contaminated batches as a precautionary Xyntha®, developed factor VIII inhibitors, measure. which are antibodies that counteract treatment with factor VIII. No reports of similar severe adverse reactions as seen in the USA have been Reference: FDA News, 21 February 2008 at reported to the MPA. The batches of http://www.fda.gov Klexane® that have not been withdrawn can be used according to the approved Esomeprazole magnesium indications. They do not contain any approved for children impurity. United States of America — The Food Reference: Medical Products Agency, 29 April and Drug Administration (FDA) has 2008. http://www.lakemedelsverket.se/Tpl/ approved esomeprazole magnesium NewsPage____7312.aspx (Nexium®) for short-term use in children 1–11 years of age for the treatment of Recombinant antihemophilic gastroesophageal reflux disease (GERD). factor approved The agency approved Nexium® in two forms, a delayed-release capsule and United States of America — The Food liquid form, in 10 mg or 20 mg daily for and Drug Administration (FDA) has children 1–11 years old compared to 20 licensed a treatment for hemophilia A, a mg or 40 mg recommended for pediatric rare, hereditary blood-clotting disorder patients 12–17 years of age. that affects approximately 15 000 individuals, almost exclusively males, in the Children prescribed this drug should be United States. monitored by their physicians for any adverse drug reactions. The new treatment, called Xyntha® Antihemophilic Factor (Recombinant) Esomeprazole magnesium is part of a Plasma/Albumin Free, is a genetically class of drugs known as proton pump engineered version of factor VIII inhibitors (PPIs). PPIs decrease the

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amount of acid produced in the stomach in the United States would likely be and help heal erosions in the lining of the infected at least once with rotavirus by esophagus known as erosive esophagitis. age 5. There are many different strains of rotavirus. The vaccine protects against FDA approved the use of esomeprazole rotavirus gastroenteritis caused by the magnesium in patients 1 to 11 years for G1, G3, G4, and G9 strains. short-term treatment of GERD based upon the extrapolation of data from The most common adverse reactions previous study results in adults to the reported during clinical trials were fussi- paediatric population, as well as safety ness, irritability, cough, runny nose, fever, and pharmacokinetic studies performed in loss of appetite and vomiting. paediatric patients. In one study, 109 patients 1-11 in age, diagnosed with To help ensure that Rotarix® does not GERD, were treated with esomeprazole increase the risk of intussusception, its magnesium once-a-day for up to eight manufacturer conducted a study of more weeks to evaluate its safety and tolerabil- than 63 000 infants. In that study, there ity. Most of these patients demonstrated was no increase in the risk of intussus- healing of their esophageal erosions after ception in those who received Rotarix® eight weeks of treatment. (31 673 infants) compared to those who received placebo (31 552 infants). The most common adverse reactions in children treated with esomeprazole Increased rates of convulsion and pneu- magnesium were headache, diarrhea, monia-related deaths were observed in abdominal pain, nausea, gas, constipa- the Rotarix® recipients in the intussus- tion, dry mouth and sleepiness. The ception study, however these events were safety and efficacy of Nexium® has not not observed in other studies conducted been established in children less than by the manufacturer. Although the FDA one year of age. has concluded that the available data do not establish that these events are related Reference: FDA News, 28 February 2008 at to the vaccine, the agency has requested http://www.fda.gov the manufacturer to conduct post-marketing safety studies involving more than Rotavirus vaccine approved 40 000 infants to provide additional safety information. United States of America — The Food and Drug Administration (FDA) has Reference: FDA News, 3 April 2008 at http:// announced the approval of Rotarix®, the www.fda.gov second oral US licensed vaccine for the prevention of rotavirus, an infection that causes gastroenteritis (vomiting and New version of genetically diarrhea) in infants and children. Rotarix engineered Factor VIIa is a liquid and given in a two-dose series approved to infants from 6–24 weeks of age. United States of America — The Food Although the disease is usually self- and Drug Administration (FDA) has limiting, rotavirus causes about 2.7 million approved a new formulation of the geneti- cases of gastroenteritis in US children cally engineered version of Factor VIIa, a each year — about 55 000 to 70 000 of plasma protein essential for the clotting of those require hospitalization; and be- blood. The new formulation allows the tween 20 and 60 deaths are attributed to product to be stored at room temperature it. Without vaccination, nearly every child for up to two years.

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The new formulation of NovoSeven The most commonly observed adverse Coagulation Factor VIIa (Recombinant)® reactions with NovoSeven RT® are fever, —contains sucrose and L-Methionine, bleeding, injection site reaction, joint which allow for storage at room tempera- discomfort, headache, elevations or falls ture. in blood pressure, nausea, vomiting, pain, swelling, and rash. Some elderly patients NovoSeven RT uses include treatment of experienced an increased risk of arterial hemophilia A or B; treatment of bleeding clotting when they were treated with and prevention of surgical bleeding in NovoSeven RT® outside of its approved patients with congenital Factor VII defi- indications. ciency; and prevention of surgical bleeding in patients with acquired hemophilia. Reference: FDA News, 9 May 2008 at http:// www.fda.gov

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International Pharmacopoeia

Role of The International tory product compliance, the following Pharmacopoeia in quality principles should be applied: assurance • the interpretation of a monograph must be in accordance with all general In the pharmaceutical sense, a pharma- requirements and testing methods, copoeia is an official, legally binding texts, or notices pertaining to it; publication containing recommended quality specifications for the analysis and • a product is not of pharmacopoeial determination of drug substances, spe- quality unless it complies with all the cific dosage forms, excipients and fin- requirements stated. ished drug products. A quality specifica- tion is a set of appropriate tests which will There is a practical distinction between confirm the identity and adequate purity pharmacopoeial standards and manufac- of the product, ascertain the strength or turers’ release specifications, although amount of the active substance and, both comprise sets of tests to which a when needed, performance characteris- given product should conform. Release tics. General requirements are also given specifications are applied at the time of in the pharmacopoeia on important manufacture of a pharmaceutical product subjects related to drug quality, such as to confirm its appropriate quality but they microbiological purity, dissolution testing, also need to have a predictive value, to or stability. support the notion that the manufacturer is responsible for the product during its The underlying principles of a pharmaco- entire shelf-life. In many cases, pharma- poeia are that pharmaceutical substances copoeial monographs are based on the and products intended for human use specifications developed by the manufac- should be manufactured at sites that are turers of innovator products. adequately equipped, dispose of appropriate professional and technical knowl- Therefore, pharmacopoeial specifications edge and are operated by qualified staff. are not used to launch innovator products General rules of appropriate pharmaceu- because the manufacturer’s quality tical manufacture are contained in the specifications will be evaluated by the good manufacturing practices (GMP) competent regulatory authorities using guidelines recommended by WHO (1) rigorous scientific assessment in conjunc- and/or those laid down by the competent tion with pre-clinical and clinical safety national or regional authority in the and efficacy data. It is important to note country of manufacture. that the regulatory focus has been shifting from finished dosage form quality control Protection provided by compendial to the control of the whole complex of standards will depend not only on techni- processes and procedures involved in the cal content but also to a great extent on manufacture of both active pharmaceuti- how they are used in the context of other cal ingredients (APIs) and finished dos- control measures. When pharmacopoeial age forms. The objective of a regulatory standards are used to establish regula- approval nowadays is to ensure that the

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manufacturer has built quality into the necessarily identify all possible danger- product from A to Z. In the case of a ous impurities. Pharmacopoeial methods multisource (generic) medicine, well are usually designed to catch the impuri- resourced regulatory authorities require ties that are likely to occur during the that it should contain the same active route of synthesis that has been utilized ingredients as the innovator drug and: by the originator. In case of a different route of synthesis or accidental contami- • be identical in strength, dosage form, nation with other chemicals, it may not and route of administration necessarily pick up impurities even if they • have the same use indications pose a danger to health. This is why well resourced regulatory authorities never • be bioequivalent (as a marker for base marketing authorization of therapeutic interchangeability) multisource (generic) products on quality control testing based on pharmacopoeial • meet the same batch requirements for monographs alone. In fact, pre-marketing identity, strength, purity and quality quality control testing has diminished • be manufactured under the same strict constantly and more accent is put on standards of GMP required for innovator market surveillance after the product is products. released onto the market.

In the case of multisource (generic) Pharmacopoeial monographs help to medicines, which are formulated after verify the quality and, in the case of patents and other exclusivity rights multisource (generic) medicines, they expire, pharmacopoeial monographs are may indicate pharmaceutical interchange- important as they enable manufacturers ability with the originator product. to develop products to meet the requirements of pharmacopoeial standards (both Beginnings and history of for APIs and finished dosage forms) The International Pharmacopoeia rather than elaborate their own specifica- The history of The International Pharma- tions. It should be noted that not all copoeia dates back to 1874 when the pharmacopoeias present monographs need to standardize terminology and to (quality standards) for finished dosage specify dosages and composition of forms. drugs led to attempts to produce an international pharmacopoeial compen- Pharmacopoeial standards should be dium. A first conference, called by the used in the framework of all regulatory Belgian Government and held in Brussels measures such as good manufacturing in 1902, resulted in the Agreement for the practice (GMP) inspection of the manu- Unification of the Formulae of Potent facture of active pharmaceutical ingredi- Drugs, which was ratified in 1906 by 19 ents and finished dosage forms, and countries. A second agreement, the scientific assessment of all quality specifi- Brussels Agreement, was drawn up in cations, interchangeability data and 1925 and ratified in 1929. This 41-article labelling information. Their greatest value agreement stipulated that the League of is revealed during post-marketing surveil- Nations would be responsible for the lance of the quality of multisource (ge- administrative work to produce a unified neric) medicines. pharmacopoeia, and a permanent secre- tariat of an international organization Pharmacopoeial standards have also would coordinate the work of national certain limitations. For example, testing pharmacopoeial commissions. General using pharmacopoeial methods will not principles for the preparation of galeni-

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International Pharmacopoeia milestones

1874 Discussion on Unification of terminology and composition of drugs

1902 First Conference organized by the Government of Belgium

1906 Agreement on Unification of the Formulae of Potent Drugs ratified by 19 states

1925 Brussels agreement (signed 1929)

1937 First meeting - Health Organization of the League of Nations

1947 Interim Commission of WHO takes up health-related work of League of Nations

1948 First World Health Assembly (WHA) establishing the Expert Commit tee on Unification of Pharmacopoeias

1950 WHA approved publication of Pharmacopoeia Internationalis

2006 Publication of 4th edition of The International Pharmacopoeia (3) cals, maximal doses, nomenclature, and tinue the work of the League’s Technical biological testing of arsenobenzones Commission. In 1948 the First World were included in the articles of this Health Assembly approved the establish- agreement, as was a table of dosage ment of the Expert Committee by the strengths and descriptions for 77 drug Interim Commission. In 1951 this became substances and preparations. the Expert Committee on the International Pharmacopoeia; and subsequently, in In response to repeated calls from phar- 1959, the Expert Committee on Specifica- maceutical experts in various countries tions for Pharmaceutical Preparations. that the Brussels Agreement be revised The panel of experts serving this Commit- and extended to cover an international tee was named the WHO Expert Advisory pharmacopoeia, the Health Organization Panel on the International Pharmaco- of the League of Nations set up a Techni- poeia and Pharmaceutical Preparations. cal Commission of Pharmacopoeial Experts in 1937. This first committee Managing The International comprised seven experts from Belgium, Pharmacopoeia Denmark, France, the Netherlands, Work on The International Pharmaco- Switzerland, United Kingdom, and United poeia is carried out in collaboration with States of America. members of the WHO Expert Advisory Panel on the International Pharmaco- In 1947 the Interim Commission of WHO poeia and Pharmaceutical Preparations took over the work on pharmacopoeias as well as with specialists from the previously undertaken by the Health pharmaceutical industry and other institu- Organization of the League of Nations, tions. This is followed by consultation with and set up an Expert Committee on the national and regional pharmacopoeias Unification of Pharmacopoeias to con- and a working procedure based on wide

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international consultation. The specifica- Step 7: Conduct laboratory testing, tions and general methods included in development and validation of QC specifi- The International Pharmacopoeia benefit cations. from an international worldwide validation process, using a global network of exper- Step 8: Support WHO Collaborating tise. This is undertaken with a view to Centre in the establishment of Interna- serve all 193 WHO Member States, the tional Chemical Reference Substances. global market and increasing trade around the world. This is a major differ- Step 9: Follow the consultative process: ence with other pharmacopoeias that send copies of draft specifications to provide control specifications for the Expert Advisory Panel and to specialists medicines sold within their country or for comments. region. Step 10: Discuss comments with contract Development of monographs for inclusion laboratories and WHO Collaborating in The International Pharmacopoeia Centres. Conduct additional laboratory testing to verify and/or validate specifica- Procedure tions.

Step 1: Identify specific pharmaceutical Step 11: Hold a consultation to discuss products for which quality control (QC) the comments and test results received specifications need to be developed, as feedback. obtain confirmation from all WHO parties concerned (e.g. Department of Medicines Step 12: Re-circulate draft monograph for Policy and Standards, Prequalification comments. project team and specific disease pro- grammes). Step 13: Repeat step 10.

Step 2: Provide contact details for manu- Step 14: Present final draft to the WHO facturers of the above products in col- Expert Committee on Specifications for laboration with all parties concerned. Pharmaceutical Preparations for possible formal adoption (for example, see the Step 3: Contact manufacturers to request Committee report from 2006, reference 6) provision of QC specifications and sam- . ples. If not adopted, repeat steps 11–13.

Step 4: Identify and contact QC laborato- The aim within this process is to keep the ries to collaborate in the project (2–3 number of reference standards to a laboratories depending on how many minimum, thus balancing the cost of pharmaceutical products have been analysis with identification of potential identified in step 1. Contract for laboratory health risks for users. work. Advantages of The International Step 5: Prepare the contract for drafting Pharmacopoeia the specifications and undertaking the Unlike national (and regional) pharma- necessary laboratory work. copoeias The International Pharmaco- poeia has no determined legal status and Step 6: Search for information on QC WHO Member States are free to adopt specifications available in the public and incorporate it, either in part or in domain. whole, into national legislation. Advan-

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tages of The International Pharmaco- substances, 183 monographs on dosage poeia are: forms (capsules, injections, tablets and tinctures) and 84 tests, methods, and • International validation of specifications general requirements. through an independent scientific process. A large number of national pharmacopoeias and official lists were examined • Input from WHO Collaborating Centres and assistance was also obtained from and national drug quality control labora- the International Pharmaceutical Federa- tories in the six WHO regions of Africa, tion (FIP) to determine the selection of the Americas, Eastern Mediterranean, substances and products to be described Europe, South-East Asia and Western in the pharmacopoeia. Pacific. Second edition • Collaboration with manufacturers The second edition was published in around the world, especially for new 1967 as Specifications for the Quality projects where no public standards Control of Pharmaceutical Preparations. exist. The selection of monographs and appen- • Collaboration with standard-setting dices was based largely on the availabil- organizations and parties, including ity, at the time, of specifications intended regional and national pharmacopoeias. for publication in national pharmacopoeias and in other volumes of specifica- • Networking and close collaboration with tions for pharmaceutical quality control. WHO Member States and drug regula- Specifications for 162 pharmaceutical tory authorities. preparations not included in the first edition were introduced in the second • Maintaining minimum cost of analysis edition, while 114 monographs were through use of robust test methods and deleted, based on feedback from the first minimum number of references stand- edition. New analytical methods were ards. also added. • Input and feedback from other WHO activities, such as the WHO/UNICEF/ Third edition World Bank Prequalification Project. In 1975, The International Pharmaco- poeia was re-focused on the needs of • Free for use by all WHO Member developing countries and recommended States. simple, classical chemical techniques that had been demonstrated as sound. Priority Published editions of was given to medicines that were widely The International Pharmacopoeia used throughout the world and medicines important to WHO public health pro- First edition grammes, also targeting those sub- The first edition, published with the aim of stances likely to contain impurities arising creating a worldwide, unified pharmaco- from degradation or due to difficulties in poeia, relied on collaboration with na- manufacture. Robust analytical test tional pharmacopoeia commissions for its methods and procedures were preferred preparation. It was published in two whenever applicable without compromis- volumes (1951 and 1955) and a supple- ing public health. A flexible approach was ment (1959) in English, French and employed to facilitate accessibility of Spanish, and was also translated into control specifications for less well German and Japanese. Altogether, it equipped national quality control labora- included 344 monographs on drug tories. Since 1979, the medicines appear-

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ing in The International Pharmacopoeia on Impurities arose from the inclusion of have been selected from the WHO Model information at the end of certain new List of Essential Medicines. monographs for antiretroviral substances. Such lists of known and potential impuri- The five volumes of the third edition ties that have been shown to be control- contained 62 general methods of analysis led by the tests in a monograph are likely and requirements, quality specifications to be included more widely in future. for 255 active pharmaceutical ingredients — the majority of essential drug sub- Most importantly, a new series of mono- stances in the WHO Model List of Essen- graphs has been added for antiretrovirals. tial Medicines — 65 quality specifications These monographs have been developed for pharmaceutical excipients, and 67 as part of the WHO strategy to make finished dosage forms. quality antiretroviral medicines widely available. Such specifications support the Fourth edition joint WHO/UNICEF/World Bank Prequali- The fourth edition of The International fication Project managed by WHO (3). Pharmacopoeia was published in 2006 These new monographs provide an (2). It comprises two volumes: General element of choice in relation to test Notices and monographs for pharmaceu- methods used for identification and, tical substances (A to O) are to be found where possible, a titration method for in Volume 1 and the remaining mono- assay, in line with established policy. graphs for pharmaceutical substances (P- However, in order to provide adequate X), together with those for dosage forms control of impurities, it has been found and radiopharmaceutical preparations, necessary to place reliance on HPLC. methods of analysis and the reagent sections are to be found in Volume 2. CD-ROM The fourth edition was published simulta- This new edition consolidates the texts of neously both in print and on CD-ROM (2). the five separate volumes of the third This provides users of The International edition and includes new monographs for Pharmacopoeia with a choice of format antiretrovirals together with updates and with which to consult the publication revisions of the existing, previously depending on the circumstances and the published texts. Significant changes and type of enquiry. The response from users improvements have been made in the of the CD-ROM has demonstrated the presentation, cross-referencing to general usefulness of making the publication methods. available electronically. The simplified structure of the fourth edition and the The new notice on Definition, for exam- improved functionality of the CD-ROM will ple, serves to define dosage forms as facilitate both reading and searching text. being manufactured with active ingredients of pharmacopoeial quality and to Future role of The International clarify the mandatory status of certain Pharmacopoeia statements in monographs. The new Work is in progress on the preparation of notice on Manufacture governs the new monographs for antiretroviral sub- interpretation of statements included stances, the associated dosage forms under this heading in monographs such and for a number of fixed-dose combina- as the general monographs for dosage tion products for the treatment of HIV/ forms, the monographs for the different AIDS, malaria and tuberculosis. Special grades of water and certain other indi- attention is also being given to paediatric vidual monographs. The need for a notice formulations.

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Revision of monographs is also continu- gives advice on good manufacturing ing to improve specifications, for exam- practices and other regulatory issues, ple, by providing better means of impurity following the underlying principle that control or by the addition of a dissolution quality must be built into a product from test. Additions and revisions to the fourth the very beginning of the manufacturing edition will be made available at appropri- process. ate intervals. There is also a close link with the Interna- Meanwhile, attention is drawn to the tional Nonproprietary Names (INN) WHO Medicines website (htpp:// programme which is responsible for www.who.int/medicines), where texts of naming new pharmaceutical entities. The monographs adopted by the Expert lists of International Nonproprietary Committee on Specifications for Pharma- Names are published in a regular manner ceutical Preparations are provided (3). The whole area of work is overseen together with other detailed information. by the WHO Expert Committee on Speci- fications for Pharmaceutical Preparations. International Chemical The WHO Expert Committee on Specifi- Reference Substances cations for Pharmaceutical Preparations International Chemical Reference Sub- is an advisory body on quality assurance stances (ICRS) are primary chemical to WHO and its Member States. Advice reference standards. They are supplied and recommendations provided by this for use in physical and chemical tests and Expert Committee are intended to support assays described in the specifications for national and regional authorities (in quality control of drugs published in The particular drug regulatory authorities), International Pharmacopoeia or proposed procurement agencies, and international in draft monographs. The ICRS may be bodies and institutions such as the Global used to calibrate secondary standards. Fund, and international organizations such as UNICEF, to combat problems of Analytical data on ICRS are given in counterfeit and substandard medicines certificates enclosed with the reference and underpin important WHO initiatives. substances. ICRS may also be used in tests and assays not described in The Conclusion International Pharmacopoeia. The re- The role of WHO in quality assurance of sponsibility for assessing the suitability of medicines, especially for those countries the reference substances then rests with that have no or little means to develop the user. their own quality control specifications, is important. WHO has numerous activities For ordering information, please visit the to support Member States such as website of the WHO Collaborating Centre creating nomenclatures and developing for Chemical Reference Standards: http:// guidance, while also delivering training www.apl.apoteket.se/who. courses and workshops on various topics of quality assurance to build national Links to other WHO activities capacity to regulate medicines. The An important feature of The International International Pharmacopoeia in conjunc- Pharmacopoeia is that it forms a basic tion with International Chemical Refer- element of quality assurance activities. ence Substances are regarded as essen- WHO gives advice on the establishment tial tools in the overall framework of and management of national quality quality control and quality assurance of control laboratories, prepares guidelines pharmaceuticals, thus contributing to the on functioning, publishes guidance and safety and efficacy of drugs.

119 The International Pharmacopoeia WHO Drug Information Vol 22, No. 2, 2008

References 3. Prequalification Programme. Web site: http://mednet3.who.int/prequal/ 1. World Health Organization. Quality assurance of pharmaceuticals. A compendium of 4. World Health Organization. Expert Commit- guidelines and related materials, Volume 2, tee on Specifications for Pharmaceutical 2nd update. Good manufacturing practices Preparations. Fortieth report. Technical Report and inspection. 2007 (388 pages) Series, No. 937. 2006 (461 pages)

2. World Health Organization. The Interna- 5. World Health Organization. International tional Pharmacopoeia, 4th edition (also nonproprietary names (INN) for pharmaceuti- available on CD-ROM). Volume 1: general cal substances. CD-ROM, 2007 (web site: notices; monographs for pharmaceutical http://bookorders.who.int/bookorders/anglais/ substances (A–O). Volume 2: monographs for qsearch1.jsp?sessla pharmaceutical substances (P–Z); monographs for dosage forms and radiopharmaceutical preparations; methods for analysis; reagents , 2006 (1499 pages)

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