LJM 1993-2820 1819-6357 Libyan Journal of Medicine, Vol. 5, No. 0, December 2010, pp. 1–9 sici xxx PUBMED Abbreviation Asma AbubakrMustafa

*Asma Abubakr Mustafa, Department of Pharmaceutics, Faculty of Pharmacy, Al-Arab Medical University,BenghaziLibya

Stefan RobertKowalski Department of Pharmaceutics, Faculty of Pharmacy Al-Arab Medical University

BenghaziLibya

The School of Pharmacy and Medical Sciences The University of South Australia

AdelaideAustralia

Libyan Journal of Medicine Analysis of LPLEM and WHO model list of essential medicines Aim and Objectives: To examine the concordance of the Libyan Pharmaceutical List of Essential Medicines (LPLEM) with the World Health Organization Model List of Essential Medicines 2009 (WMLEM 2009). Methods: The concordance between generic medicines listed in the WMLEM 2009 (standard reference list) and the LPLEM 2006 (comparator list) was evaluated. Results: The total number of Basic Essential Medicines (BEMs) listed on the WMLEM 2009 was 347. The total number of generic medicines listed on the LPLEM was 584. Although the LPLEM has more listed medicines, only 270 (77.6%) of BEMs from the WMLEM were listed as available. However, 25 of the 77 missing medicines were deemed to have appropriate alternatives. A total of 52 medicines from the WMLEM 2009 were therefore missing from the LPLEM. Discrepancies compared to the WMLEM 2009 were identified in 15 out of 29 therapeutic sections. The highest discrepancy rate from the WMLEM 2009 was in the anti-infective section (35 missing medicines). Missing BEMs were noted in many subclassifications of the anti-infective medicines section, but omissions were particularly prevalent in the antibacterial medicines subsection (11 missing medicines). Antituberculosis medications had the highest discrepancy rate for antibacterial BEMs with one-third of the single medicines recommended by the WHO in the WMLEM 2009 not listed on the LPLEM. Of the 314 additional medicines on the LPLEM, 18 were deemed to be irrational non-essential medicines. Conclusion: The LPLEM does not include several essential medicines recommended by the WHO in the WMLEM 2009. These discrepancies may have serious public health implications for management of some infectious diseases, particularly, tuberculosis and HIV. essential medicines medicine selection national medicines policy pharmaceuticals policy formulary list A National Essential Medicines List (NEML) is central to the sound management and supply of essential medicines to any society 1. Appropriate selection of essential medicines for a NEML has been considered by the World Health Organization (WHO) as the most cost-effective health intervention after childhood immunization 2. The appropriate selection of medicines can assist with the management and supply of medicines and, as a result, curb the financial burden caused by pharmaceuticals on national health budgets 3. According to the WHO, a NEML should encompass a limited group of medicines that are of proven safety, efficacy, and cost effectiveness 4. This limited group of medicines has been named by the WHO as essential medicines 2. Under ideal circumstances essential medicines are defined within the national context and according to the prevalent diseases and conditions in a given society 5. Since this capacity is limited in many developing countries 1, the WHO has identified a subset of medicines to treat the world's most common diseases and conditions. This subset of medicines is listed in the WHO model list of essential medicines (WMLEM) and has been regularly updated since 1977. Essential medicines listed in the WMLEM represent the minimum number of medicines that should be available within any fully functioning health care system and need to be the foundation of any NEML 26.Libya is an upper middle-income North African nation that strives for high standard health care services 7. Historically, the Libyan national standard list of medicines was used by the public pharmaceutical sector of the Libyan health care system 89 for the procurement and government subsidy of medicines for Libyan society. Medicines are also supplied by the private pharmaceutical market; however, access to medicines from the private market is often prohibitively expensive.The Libyan national standard list of medicines, which was commonly known as the Libyan Pharmaceutical List (LPL), was previously the list of all registered medicines used in the Libyan health care system 8. Since the LPL was too extensive to use for the general procurement of medicines, government subsidy, and also encompassed several unsafe and superseded medicines, it had been implicated by local researchers 89 and the WHO 7 as a contributor to the problem of medicines management and supply in Libya. As a result, the LPL was cancelled by the National Committee of Drugs 7 and replaced by a new Libyan national standard list of medicines – the Libyan Pharmaceutical List of Essential Medicines (LPLEM) in 2006. According to the Directorate of Pharmacy and Medical Equipment in the Libyan Ministry of Health, the LPLEM 2006 encompassed only essential medicines (rather than all registered medicines in the health system) as advocated by the WHO. The LPLEM 2006 continues to be the current Libyan national standard list for procurement and government subsidy of medicines.The continuing problem of medicines management and supply to Libyan society has been acknowledged by the Libyan Government in several recent press releases 10. Therefore, the aim of this study was to examine the LPLEM 2006 in relation to compliance with the WHO recommendations for medicines selection in order to identify or exclude the LPLEM 2006 as a potential contributor to the suboptimal management and supply of essential medicines in Libya. The concordance between the WMLEM 2009 and the LPLEM 2006 was compared based on the method utilized by Jafarov 11. All medicines listed in the WMLEM 2009 were considered as Basic Essential Medicines (BEMs) since they represent the minimum formulary of medicines that should be available for a country's health care system. Both the core medicines list and complementary medicines list were reviewed. The core medicines list details medicines that meet the minimum needs for a basic health care system, whereas the complementary medicines list catalogues drugs used for priority diseases for which specialized diagnostic or monitoring facilities, specialist medical care, and/or specialist training are needed. The WMLEM 2009 was used as the standard reference list for comparison (including the therapeutic sections) and the LPLEM 2006 was the subject list. Since both lists were not fully super imposable, a spreadsheet was constructed to allow head-to-head comparison. Information in relation to both lists was inserted in a comparative matrix that allowed for evaluation of available BEMs (medicines from the WMLEM 2009 that were available on the LPLEM based on generic name), missing BEMs (medicines from the WMLEM 2009 that were not available on the LPLEM based on generic name), additional available medicines (medicines on the LPLEM but not listed on the WMLEM 2009), or alternative available medicines. A medicine was deemed by the reviewers to be an alternative available medicine to a listed BEM from the WMLEM 2009 based on either being in the same pharmacological class (e.g. tetracaine and oxybuprocaine) or if having an ‘equivalent’ therapeutic action (e.g. DL-methionine and N-acetylcysteine).If a medicine was listed in more than one therapeutic section (e.g. morphine was listed in both the analgesics and anesthetics sections) or was available in an alternative therapeutic section, the medicine was recorded as available. For available BEMs, the number of product formulations and strengths were identified and reconciled as follows: Available BEMs that were presented in the LPLEM in total concordance with those recommended by the WHO in the WMLEM 2009. Available BEMs that were presented in the LPLEM with less or more dosage forms and/or product strengths than those recommended by the WHO in the WMLEM 2009. The total number of medicines listed in the WMLEM 2009 was 347. The total number of medicines listed on the LPLEM was 584. Based on generic identification of counterparts from both lists, the LPLEM complied fully with the recommendations of the WHO with regards to essential medicines in 14 of the 29 standard therapeutic sections. Detailed information in relation to number of available BEMs per therapeutic section is illustrated in Table 1. Therapeutic section Medicines from the WMLEM 2009 (BEMs) Number of BEMs that are not listed on the LPLEM (Missing BEMs) ^aDuplicates exist among different therapeutic sections. ENT: ear, nose, and throat. Analgesia 11 0 Anesthesia 13 1 Antiallergic 5 0 Antidotes 14 4 Antiepileptic 8 0 Anti-infective 107 37 Antimigraine 4 0 Antineoplastic 28 0 Antiparkinsonian 2 0 Blood products 4 0 Cardiovascular 19 0 Dermatological 21 10 Diagnostic agents 6 0 Disinfectants 6 1 Diuretics 5 0 Electrolytes and water 8 0 Endocrine 21 6 ENT conditions in children 4 2 Gastrointestinal 14 3 Hematinics 8 0 Immunological 26 3 Muscle relaxants 5 1 Ophthalmological 10 1 Oxytocics 5 1 Peritoneal dialysis 1 0 Psychotropic 12 3 Respiratory 5 0 Specific medicines for neonatal care 4 1 Vitamins and minerals 11 3 Total^a 387 77 From the list of 347 BEMs on the WMLEM 2009, only 270 (78%) BEMs were listed as available on the LPLEM. Based on direct generic medicine concordance with the WMLEM 2009, 77 (22%) of medicines recommended by the WHO in the WMLEM 2009 were therefore missing from the LPLEM (missing BEMs). However, for 25 (32%) of these missing BEMs therapeutic, alternatives were available via another known channel of supply within the Libyan health system, were culturally unacceptable, or irrelevant to the Libyan disease demographic. In more detail: Eight (10%) of the missing BEMs have therapeutic alternatives on the LPLEM. Of these, five had alternatives that are chemically different but are from the same pharmacological class (e.g. tetracaine and oxybuprocaine), while three BEMs had an alternative drug that could be considered therapeutically similar (e.g. DL-methionine and N-acetyl cysteine). Some medicines from the dermatological section (n=7), endocrine section (n=1), vitamins and minerals section (n=1), and the ear nose and throat conditions in the children section (n=1) were not listed on the LPLEM. However, these products are available on request as extemporaneously manufactured products (e.g. potassium permanganate 1 in 10,000 solution, benzoic acid 3%/Salicylic acid 6% ointment, etc.) and have therefore been omitted from the missing BEMs group (see Table 2). Some endocrine contraceptives products (n=3) and oxytocics (n=1) are not included on the LPLEM for cultural or legal reasons (see Table 2). Some therapeutic substances (oxygen gas and ethanol) are supplied by other Libyan government bodies of medical supply 9. The Japanese encephalitis vaccine (n=1) is irrelevant to the Libyan national disease profile. In summary, there were 52 missing BEMs from the WMLEM 2009 that were not listed as available on the LPLEM. Theses medicines are listed in Table 3. Therapeutic section Number Missing BEMs Alternatives ^aAvailable via other channels of supply for medical equipment and chemicals. ^bAvailable as an extemporaneous preparation. ENT: ear, nose, and throat. Anesthesia 1 Oxygen gas Supplied by alternate provider^a Antidotes 1 DL-methionine N-acetylcysteine Anti-infective 2 Cefotaxime Ceftazidime Ceftriaxone Imipenem + Cilastin Meropenem Dermatological 7 Benzoic acid + salicylic acid Gentian violet Potassium permanganate Calamine lotion Coal tar Salicylic acid Urea Extemporaneous preparation^b Disinfectants 1 Ethanol Supplied by alternate provider^a Endocrine 3 Diaphragms with spermicide (nonoxinol) Condoms with or without spermicide (nonoxinol) Copper-containing device Private sector based on cultural reasons 1 Lugol's solution Extemporaneous preparation^b ENT conditions in children 1 Acetic acid Extemporaneous preparation^b Gastrointestinal 2 Aluminum hydroxide Magnesium hydroxide Magnesium trisilicate 250 mg with dried aluminum hydroxide gel 100 mg tabs Immunologicals 1 Japanese encephalitis vaccine Irrelevant to Libyan morbidity profile Ophthalmological 1 Tetracaine Oxybuprocaine Oxytocics 1 Mifepristone-misoprostol Culturally unacceptable Psychotropic 1 Fluphenazine decanoate Flupenthixol decanoate Vitamins and minerals 2 Riboflavin Vitamin B complex Iodine Extemporaneous preparation^b Total 25 Therapeutic section Medicines from the WMLEM 2009 (BEMs) Number of missing BEMs Missing BEMs ENT: ear, nose and throat. Potassium ferric hexacyano-ferrate(II) 2H₂O (Prussian blue) Antidotes 14 3 Sodium nitrite Sodium thiosulfate Anti-infective 107 35 Multiple/Table 4 Dermatological 21 3 Aluminum diacetate Selenium sulfide Permethrin Endocrine 21 2 Ethinylestradiol Estradiol cypionate + medroxyprogesterone acetate ENT conditions in children 4 1 Xylometazoline Gastrointestinal 14 1 Zinc sulfate Immunologicals 26 2 Varicella vaccine Rotavirus vaccine Muscle relaxants 5 1 Alcuronium chloride Psychotropic 12 2 Methadone Nicotine replacement therapy Specific medicines for neonatal care 4 1 Caffeine citrate Vitamins and minerals 11 1 Thiamine 52 Missing BEMs (see Table 3) were distributed over 15 out of 29 standard therapeutic sections with the highest number of missing medicines in the anti-infective section (n=35). Missing BEMs from the anti-infective medicines section (see Table 4) were distributed over various subsections with the highest recorded discrepancy in the antibacterial medicines subsection (n=11). One-third of antituberculosis medications recommended by the WHO in the WMLEM 2009 were not listed on the LPLEM. In addition, all fixed dose combinations recommended by the WMLEM were not listed on the LPLEM. Therapeutic subsection Total number of medicines listed in the WMLEM 2009 Number of missing medicines Missing medicines Anthelminthics 11 7 1. Levamisole 2. niclosamide 3. Pyrantel 4. ivermectin 5. suramin sodium 6. triclabendazole 7. Oxamniquine Antibacterial 48 11 1. cefazolin 2. Cefixime 3. isoniazid + ethambutol 4. rifampicin + isoniazid + pyrazinamide + ethambutol 5. rifampicin + isoniazid + ethambutol 6. rifampicin + isoniazid + pyrazinamide 7. rifampicin + isoniazid 8. Rifabutin 9. Ethionamide 10. Kanamycin 11. p-aminosalicylic acid Antifungal 7 1 1. flucytosine Antiviral medicines 21 7 1. emtricitabine(FTC) 2. tenofovir disoproxil fumarate(TDF) 3. efavirenz + emtricitabine + tenofovir 4. emtricitabine + tenofovir 5. stavudine + lamivudine + nevirapine 6. zidovudine + lamivudine + nevirapine 7. ribavirin Antiprotozoal 25 9 1. paromomycin 2. Amodiaquine 3. Artemether 4. Proguanil 5. Sulfadiazine 6. Eflornithine 7. Melarsoprol 8. Nifurtimox 9. benznidazole Total 112 35 Six out of seven missing BEMs from the antiviral subsection were antiretroviral medicines. Of these, four were fixed dose combinations and two were single medicines. Nine medicines were also missing from the antiprotozoal subsection. After review there were 314 medicines on the LPLEM deemed to be additional. Of these, 274 were classified under the same therapeutic sections adopted by the WHO in the WMLEM 2009. However, of these 274 medicines, 18 were deemed by the reviewers to be non-essential medicines (see Table 5). Forty of the additional medicines listed on the LPLEM fall outside the perimeters of the classification system for BEMs used by the WHO. These products include dietary supplements, pharmaceutical chemicals, and rodenticides. Antibiotic and corticosteroid combinations in the eye section (four different products) Nicoumalone 1 mg tablet Antihemorrhoidal ointment Noscapine linctus 15 mg/5ml 100 ml bottle Antihemorrhoidal with hydrocortisone Pentazocine 25 mg tablets Chlordiazepoxide 5 mg with clidinium bromide 2.5 mg tablets Pentazocine lactate 30mg/ml ampoules Clomethiazole 192 mg in oily base capsules Ritodrine hydrochoride 10 mg tablets Dihydrocodeine tartarate 30 mg tablets Ritodrine hydrochoride 10 mg/5ml ampoules Ethanolamine oleate 5% 5 ml ampoules Tetracycline 250 mg capsules Maprotiline hydrochloride 75 mg tablets Thiocetazone 100 mg tablets Mercurochrome Tiaprid 100 mg tablets Nalidixic acid 500 mg tablets Trometamol 7% solution Of 270 available BEMs, 172 were presented in the LPLEM in total concordance with those recommended by the WHO in the WMLEM 2009, 67 were presented in the LPLEM with less dosage forms and/or product strengths than those recommended by the WHO in the WMLEM 2009, and 31 were presented in the LPLEM with more dosage forms and/or product strengths than those recommended by the WHO in the WMLEM 2009. According to the WHO guidelines, a NEML is central to medicine's management and supply for any society 1. However, in order for a NEML to contribute positively to the national medicines situation, medicines on the list must first be selected appropriately. Full discussion of the ideal process of medicines selection is beyond the scope of this paper. However, the WHO states that appropriate selection of medicines for a NEML is a process that requires several tenets to be carefully considered 2. Firstly, medicines need to be selected from a pool of safe and effective medicines underpinned by a sound medicine registration system 1. Secondly, medicines on the NEML should reflect the treatment requirements of nationally prevalent diseases that have been identified and examined by a robust epidemiological reporting process. In order for national decision makers to act accordingly, national health indicators that reflect morbidity and mortality trends must be available 2. In addition, other supportive measures need to be implemented. A national system to identify microbial resistance patterns, as well as educational and government processes to provide personnel well trained in current therapeutics, morbidity trends, critical appraisal, and pharmacoeconomics 12 need to implemented. As stated by local researchers, the capacity to perform such tasks in Libya needs to be improved 89.Since epidemiological data regarding the Libyan national disease profile is not readily available 713, the LPLEM was evaluated in comparison to the WMLEM as a potential contributor to medicine availability problems in Libya. The WHO recommends that all medicines listed on the WMLEM be available in any fully functioning health system 2 unless the medicine is legally unacceptable, culturally improper, or irrelevant to the national disease profile 14. The analysis demonstrated that the LPLEM fully complied with medicines recommended by the WHO in the WMLEM 2009 in 14 out of 29 therapeutic sections. However, many BEMs were not listed as available in other therapeutic sections. Even after considering possible therapeutic alternatives, there were 52 missing BEMs from the LPLEM. There was one BEM not listed in the gastrointestinal, muscle relaxant, vitamins and minerals, specific medicines for neonatal care, and medicines for ear nose and throat conditions in children therapeutic sections; two BEMs not listed in the endocrine, immunological, and psychotropic therapeutic sections; and three BEMs not listed in the antidotes and dermatological therapeutic sections.The area of greatest concern was the anti-infective section, where 35 medicines from the WMLEM were not listed on the LPLEM. The WHO states that several communicable diseases such as tuberculosis, HIV/AIDS, malaria, and leishmaniasis still impose a threat to Libyan society 713It is important to reinforce that risks imposed by suboptimal anti-infective medicine selection have the capacity to extend well beyond an individual patient 15. The LPLEM was suboptimal in relation to inclusion of essential anti-infective medicines from the WMLEM 2009 for all subsections of anti-infective medicines. The highest recorded discrepancy from the anti-infective section was with antituberculosis medicines (see Table 4). Antituberculosis medicines recommended in the WMLEM 2009 are either single medicines or fixed dose combinations. Four single medicines, including the first-line antituberculosis medicine, rifabutin, were not listed on the LPLEM. Five first-line antituberculosis fixed dose combinations were also not listed on the LPLEM (see Table 4). Although all individual medicines included in these fixed dose combinations were listed on the LPLEM, this does not necessarily provide the best mechanism to ensure treatment effectiveness, patient compliance, and does not eliminate the need for fixed dose combinations 1617. Fixed dose combinations of antituberculosis medicines offer several advantages since they reduce the number of capsules or tablets that must be ingested daily, decrease the likelihood of resistance, improve clinical outcomes, enhance patient compliance, simplify treatment regimens, and facilitate logistics 161819. Fixed dose combinations can only be excluded in settings where the WHO recommendations in relation to tuberculosis treatment (e.g. the Directly Observed Short Course, DOTS, strategy) are strictly implemented 1718. Nevertheless, even in such settings, fixed dose combinations enhance patient compliance by decreasing ‘pill burden’ 18. The importance of providing the best available pharmaceutical products, including fixed dose combinations to treat tuberculosis, is reinforced by evidence of a substantial increase in the number of reported tuberculosis cases over the last 15 years in Libya 20. In addition, although information from the WHO Libyan country profile 13 indicates the existence of multidrug resistant tuberculosis, three out of seven treatments recommended by the WHO for the treatment of multidrug resistant tuberculosis were not listed on the LPLEM. Also of concern is the continued listing of thiocetazone (as an additional medicine antituberculosis in the medicines section on the LPLEM), a drug whose use is diminishing due to safety concerns and questionable efficacy 21. Thiocetazone has weak activity against Mycobacterium tuberculosis and offers no advantage over ethambutol 22.Results from the comparative analysis demonstrated another major discrepancy in the antiretroviral medicines section. HIV/AIDS is not currently a major cause of morbidity and mortality in Libya, however its incidence is increasing among injecting drug users 7. Two single as well as four fixed dose combinations were missing from the LPLEM (see Table 4). As with tuberculosis treatment, fixed dose combinations reduce pill burden, minimize (prescribing, dispensing, and use) errors, and improve logistics 23. Triple antiretroviral combinations employing fixed dose combinations are the most convenient and affordable options for treatment 16.The analysis of the antiprotozoal subsection demonstrated that one of three BEMs (paronomycin) used for the treatment of leishmania infections (see Table 4) is missing from the LPLEM. Leishmaniasis is endemic in some areas of the Libyan nation 24 and is an increasing problem not only in Libya but also in the whole African continent 10. Three BEMs used to treat malaria are also not listed on the LPLEM. Although malaria is not a major disease problem in Libya 7 since isolated cases still require treatment, all BEMs to treat malaria should be available.Missing BEMs from the LPLEM that have implications for children and neonatal care (n=4), include caffeine citrate and rotavirus vaccine. Caffeine citrate is preferred to aminophylline for the treatment neonatal apnea of prematurity due to a better adverse effect profile and a , a longer elimination half-life 25, and hence should also be listed on the LPLEM. Rotavirus vaccine is a major cause of childhood diarrhea in Libya 26 and is highly recommended by the WHO to be included in national immunization programs. Clinical trials of rotavirus vaccine in high-mortality, low-socioeconomic settings of South Africa and Malawi have found that the vaccine significantly reduced severe diarrhea episodes due to rotavirus 27.Another area of concern is antidote medicines. Although uncommon, thallium and cyanide poisonings are potentially life threatening 2829. Prussian blue, the antidote of choice for treatment of thallium toxicity 30 as well as sodium nitrite and sodium thiosulfate to treat cyanide poisoning 31, need to be listed on the LPLEM.Of 21 dermatological medicines, 3 were missing from the LPLEM (see Table 4). The inclusion of malathion on the LPLEM (within the group of additional medicines) does not eliminate the need for permethrin. No significant difference exists in regarding their efficacy against head lice 32 and permethrin requires less application time and is a safer alternative in most cases.The 2002 definition of essential medicines 2 clearly states that there is no upper limit for inclusion of medicines on a NEML; however, the definition set out by the WHO clearly indicates that the optimization of essential medicines be the principal priority 2. The LPLEM included a high number of additional medicines (n=274) that exceeded the number of essential medicines on the list (n=270). This group of additional medicines on the LPLEM included some medicines that were deemed to be non-essential. Some of the non-essential medicines could be considered obsolete since newer alternatives from the same class exist on the LPLEM. Specific examples include nalidixic acid and tetracycline. Nalidixic acid has been superseded by other quinolones 33 while doxycycline has largely replaced tetracycline worldwide 34. The inclusion of the fixed dose combination of chlordiazepoxide and clidinium bromide cannot be justified in 2010 as a necessary product for a NEML. The LPLEM also included additional medicines with poor safety profiles such as maprotiline, a third-line tetracyclic antidepressant with a higher epileptogenic potential than many alternative antidepressants available on the LPLEM 35.This study of the generic concordance of medicines between the LPLEM and the WMLEM 2009 did not reconcile product (dosage forms and dosage strengths) discrepancies among both lists. For example, pyrazinamide was deemed as an available BEM on the LPLEM; however, pyrazinamide was listed only as a 500 mg tablet, whereas the WMLEM 2009 recommends multiple formulations and strengths (30 mg/ml oral liquid, 400 mg tablet, 150 mg dispersible tablets, and 150 mg scored tablets). The review of appropriate dosage form and strength selection is also an important aspect of rational selection of medicines for NEMLs that requires further research.The discrepancies between the LPLEM 2006 and the WMLEM 2009 highlight the need for continual review of the LPLEM. Future discrepancies can be prevented if the list is reviewed continually or at least annually. This analysis of the LPLEM in reference to the WMLEM 2009 has several implications for medicines management and supply in Libya. In order to cater for the essential medicines needs of the Libyan health system, all aspects of appropriate medicine selections advocated by the WHO need to be considered. The establishment of a standardized evidence-based process of medicines selection that complies with the WHO recommendations is the one and only avenue that can systematically build a robust NEML that fulfils the societal needs of medicines. The anti-infective section in the LPLEM has demonstrated the highest discrepancy from the WHO recommendations and requires urgent review. In addition, the LPLEM still includes several medicines with safety concerns or with minimal evidence of clinical efficacy. 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