Abstract
BACKGROUND:
The concept of listing essential medicines can lead to improved supply and access, more rational prescribing, and lower costs of drugs. However, these benefits hinge on the prescription of drugs from an Essential Medicines List (EML). Several studies have highlighted the problem of underutilization of EMLs by prescribers. Therefore, as part of prescription research by the Indian Council of Medical Research-Rational Use of Medicines Centres Network, we evaluated the extent of prescription of drugs not listed in the National List of Essential Medicines (NLEM).
MATERIALS AND METHODS:
Prescriptions of outpatients from participating centers were included after obtaining verbal/written informed consent as approved by the Ethics Committee, and evaluated for prescription of drugs from the NLEM 2015.
RESULTS:
Analysis of 4838 prescriptions from 13 tertiary health-care institutes revealed that 2677 (55.33%) prescriptions had at least one non-NLEM drug prescribed. In all, 5215 (31.12%) of the total 16,758 drugs prescribed were not in NLEM. Of these, 2722 (16.24%) were single drugs and 2493 (14.88%) were fixed-dose combinations (FDCs). These comprised 700 different drug products – 346 single drugs and 354 FDCs. The average number of non-NLEM drugs prescribed per prescription was 1.08, while the average number of all drugs prescribed was 3.35 per prescription. It was also found that some of the non-NLEM drugs prescribed had the potential to result in increased cost (for example, levocetirizine), increased adverse effects (dextromethorphan), and less effectiveness (losartan) when compared to their NLEM counterparts. Nonavailability of an essential drug (oral hydroxocobalamin) was another important finding of our study.
CONCLUSION:
This study highlights the extent and pattern of drugs prescribed from outside the NLEM at the tertiary health-care level and the need for training and enhanced awareness among prescribers for greater utilization of the NLEM.
Keywords: Audit, drugs, medicine, National List of Essential Medicines, rational use
Introduction
The Indian Council of Medical Research (ICMR) established the National Virtual Centre of Clinical Pharmacology and approved 15 Rational Use of Medicines Centres (RUMCs) as a Task Force Project in August 2019, with the objectives of conducting prescription research and developing a prescribing skills course.[1] In September 2020, the online prescribing skills course for Indian medical graduates was launched.
To analyze real-world problems in prescribing and use these as pointers toward areas of focus in the course, a nationwide prescription evaluation study was carried out in 13 tertiary health-care institutes which are part of the ICMR-RUMC Network. Outpatient prescriptions were evaluated for appropriateness of drugs prescribed, use of irrational and banned fixed dose combinations (FDCs), and prescription of drugs from outside the National List of Essential Medicines (NLEM). This paper reports the analysis of prescription of drugs from outside the NLEM.
In 1977, at the first meeting of the Expert Committee on Selection of Essential Drugs, the World Health Organization (WHO) adopted the first Model List of Essential Drugs. The WHO defines essential drugs as “those drugs that satisfy the healthcare needs of majority of the population.”[2] In India, the first NLEM was prepared in 1996, the current list was published in 2015, and an update is in process.
However, the selection and availability of essential medicines are only the initial steps toward improving the quality of health care. They are of no use unless prescribed correctly. Unfortunately, many studies on drug utilization and prescription patterns have highlighted the problem of underutilization of Essential Medicines Lists (EMLs).[3] The problem is not unique to our country, but prevalent across the globe, and is particularly important in developing countries.
As part of prescription research under the ICMR Task Force Project on Rational Use of Medicines, we therefore undertook to evaluate the extent of prescription of drugs not listed in the NLEM, to provide inputs to the prescribing skills training program. Further, the NLEM 2015 is under revision, and the findings of this study may provide valuable inputs as to certain drugs which may need to be included (if justified) in an updated version.
Materials and Methods
Study design
This was a cross-sectional prescription analysis.
Study site
The study was conducted at 13 tertiary health care centers across the country which are a part of the ICMR-RUMC Network under the ICMR Task Force Project on Rational Use of Medicines.
Sample size
As per the WHO guidelines for investigating drug use in a health facility,[4] the goal of a drug use study should be to estimate percentage indicators that summarize values for the sample as a whole with a 95% confidence interval of ± 7.5%. This requires that at least 600 encounters should be included in a survey.[4] Thus, we aimed at collecting data from 600 prescriptions per center so that each center could analyze the data in the context of its own setting as well as pool the data for a nationwide analysis.
Data collection
Prescriptions of patients of either gender and any age group exiting from the various outpatient departments (OPDs) or hospital pharmacy were included. Since one of the broader objectives of the project was to assess the appropriateness of prescribed drugs, only prescriptions with signs and symptoms and a provisional diagnosis were included in the study. Data from a prescription was captured by photographing the prescription with the help of a mobile phone, or by filling out the case record form directly. The study duration was 1 year, from August 2019 to August 2020.
Data analysis
Descriptive statistics were used to analyze the data. The National List of Medicines (NLEM), India, 2015[5] was the basis to assess whether the drugs prescribed were listed in the NLEM. A drug was considered not included in NLEM if a salt other than that listed in NLEM 2015 was prescribed. Single drugs prescribed in a dosage form or strength differing from that listed in NLEM were also counted as non-NLEM drugs but under a separate category. Tablets and capsules were considered the same dosage forms.
Fixed-dose combinations (FDCs) (one FDC was counted as one drug) were considered not included in the NLEM even if all or some of the components were listed separately in the NLEM, but not as an FDC. An FDC component was considered included in NLEM even if listed in NLEM in a different strength or dosage form (but as the same salt).
Data are presented as number of drug products, number of drugs prescribed, and number of prescriptions containing them.
Ethical considerations
Prescriptions from patients were included only after the patient or their legally authorized representative had given written or verbal consent as per the approval of the Ethics Committee at each center. Patients were not interviewed, and no other patient records were accessed. Patient confidentiality was strictly maintained. The study was approved by the Institutional Ethics Committees of each of the participating centers.
Results
During the study period from August 2019 to August 2020, we captured and analyzed 4838 prescriptions from 13 tertiary health-care institutes across India. Some centers could not reach the target of 600 prescriptions due to the outbreak of the COVID-19 pandemic. The number of prescriptions from centers ranged from 78 to 678, with an average of 372 prescriptions per center [Annexure I]. There were 2677 (55.33%) prescriptions in which at least one non-NLEM drug was prescribed. The average number of non-NLEM drugs prescribed per prescription was 1.08, while the average number of all drugs prescribed per prescription was 3.35.
In all, 5215 (31.12%) of the total 16,758 drugs prescribed were not listed in the NLEM. Of these, 2722 (16.24%) were single drugs and 2493 (14.88%) were FDCs [Table 1]. These comprised 700 different drug products – 346 single drugs and 354 FDCs.
Table 1.
Overview of drugs prescribed from outside the National List of Essential Medicines, 2015
| Non-NLEM drug product | Number of non-NLEM drug products (percentage of n=700), n (%) | Number of non-NLEM drugs prescribed (percentage of n=5215), n (%) |
|---|---|---|
| Single drug products | ||
| Not included in NLEM in any dosage form or strength | 299 (42.71) | 2156 (41.34) |
| Included in NLEM 2015 in a dosage form or strength other than that prescribed | 47 (6.71) | 566 (10.85) |
| Total | 346 (49.43) | 2722 (52.20) |
| FDCs | ||
| FDCs in which no component is included in NLEM | 113 (16.14) | 621 (11.91) |
| FDCs in which one or more component/s is/are included in NLEM | 214 (30.57) | 1354 (25.96) |
| FDCs in which all components are included in NLEM separately, not as FDC | 27 (3.86) | 518 (9.93) |
| Total | 354 (50.57) | 2493 (47.80) |
| Grand total | 700 (100.00) | 5215 (100.00) |
FDC=Fixed-dose combination, NLEM=National List of Essential Medicines
Among the 346 single drugs prescribed, 299 (42.71% of all non-NLEM drug products) were not listed in NLEM in any form, while 47 (6.71%) were listed in a different dosage form or strength [Table 1]. There were four drug products which were prescribed as salts other than the ones listed in NLEM. These included oral calcium aspartate and calcium lactate (29 or 0.60% prescriptions) instead of calcium carbonate listed in the NLEM and oral zinc acetate and topical zinc oxide (6 or 0.12% prescriptions) in place of oral zinc sulfate listed in the NLEM. Topical zinc oxide was used as a soothing and anti-inflammatory agent, while oral zinc acetate and zinc sulfate were used in diarrhea.
Vitamins and minerals were the most frequently used non-NLEM drugs both in terms of number of drugs prescribed (99 or 14.14% of all non-NLEM drug products – 8 as single drugs and 91 as FDCs) as well as number of prescriptions containing them (977 or 20.19% of all prescriptions) [Table 2].
Table 2.
Most frequently prescribed non-National List of Essential Medicines drug products and drugs prescribed as per category arranged in decreasing order of number of drug products
| NLEM section | NLEM section | Total* | Single drug | FDC* | |||
|---|---|---|---|---|---|---|---|
|
|
|
|
|||||
| Number of non-NLEM drug products (percentage of n=700), n (%) | Number of prescriptions (percentage of n=4838), n (%) | Number of non-NLEM drug products (percentage of n=700)†, n (%) | Number of prescriptions (percentage of n=4838), n (%) | Number of non-NLEM drug products (percentage of n=700)†, n (%) | Number of prescriptions (percentage of n=4838), n (%) | ||
| 30 | Vitamins and minerals‡ | 99 (14.14) | 977 (20.19) | 8 (1.14) | 135 (2.79) | 91 (13.00) | 842 (17.40) |
| 14 | Dermatological medicines | 96 (13.71) | 359 (7.42) | 47 (6.71) | 219 (4.53) | 49 (7.00) | 140 (2.89) |
| 20 | Gastrointestinal medicines | 69 (9.86) | 918 (18.97) | 27 (3.86) | 546 (11.29) | 42 (6.00) | 372 (7.69) |
| 20.1 | Antiulcer medicines | 26 (3.71) | 677 (13.99) | 7 (1.00) | 423 (8.74) | 19 (2.71) | 254 (5.25) |
| 2 | Analgesics, antipyretics, nonsteroidal anti-inflammatory medicines, medicines used to treat gout, and disease-modifying agents used in rheumatoid disorders | 59 (8.43) | 635 (13.13) | 22 (3.14) | 221 (4.57) | 37 (5.29) | 414 (8.56) |
| 2.1 | Nonopioid analgesics, antipyretics, and nonsteroidal anti-inflammatory medicines | 48 (6.86) | 555 (11.47) | 13 (1.86) | 174 (3.60) | 35 (5.00) | 381 (7.88) |
| 6 | Anti-infectives | 58 (8.29) | 329 (6.80) | 37 (5.29) | 171 (3.53) | 21 (3.00) | 158 (3.27) |
| 6.2 | Antibacterials | 41 (5.86) | 186 (3.84) | 24 (3.43) | 75 (1.55) | 17 (2.43) | 111 (2.29) |
| 12 | Cardiovascular medicines | 51 (7.29) | 268 (5.54) | 32 (4.57) | 152 (3.14) | 19 (2.71) | 116 (2.40) |
| 12.3 | Antihypertensive medicines | 30 (4.29) | 160 (3.31) | 16 (2.29) | 100 (2.07) | 14 (2.00) | 60 (1.24) |
| 28 | Medicines acting on the respiratory tract | 40 (5.71) | 298 (6.16) | 10 (1.43) | 107 (2.21) | 30 (4.29) | 191 (3.95) |
| 28.1 | Anti-asthma medicines | 24 (3.43) | 198 (4.09) | 7 (1.00) | 60 (1.24) | 17 (2.43) | 138 (2.85) |
| 3 | Anti-allergics and medicines used in anaphylaxis | 37 (5.29) | 536 (11.08) | 17 (2.43) | 373 (7.71) | 20 (2.86) | 163 (3.37) |
| 21 | Hormones, other endocrine medicines, and contraceptives | 36 (5.14) | 228 (4.71) | 25 (3.57) | 198 (4.09) | 11 (1.57) | 30 (0.62) |
| 21.4.1 | Insulin and other antidiabetic agents | 23 (3.29) | 177 (3.66) | 14 (2.00) | 157 (3.25) | 9 (1.29) | 20 (0.41) |
| Other sections | 164 (23.43) | 848 (17.53) | 93 (13.28) | 523 (10.81) | 71 (10.14) | 325 (6.72) | |
| Section not included in NLEM | 31 (4.43) | 86 (1.78) | 28 (4.00) | 77 (1.59) | 3 (0.43) | 9 (0.19) | |
| Total (excluding the sub-sections) | 740* | 5482 | 346 (49.43) | 2722 (56.26) | 394 (56.28) | 2760 (57.04) | |
*An FDC containing components from different sections was counted under each section e.g., naproxen plus domperidone was counted under sections 2.1 as well as 20. Therefore, the number of drug products will not add up to 700. †Percentages are out of total number of drug products (700) and not number of single drug products or FDCs. ‡Folic acid, Vitamin B12, and iron are listed under anti-anemia medicines in NLEM 2015. Therefore, these and their FDCs were counted as anti-anemia drugs. However, FDCs containing folic acid, Vitamin B12, and/or iron with an additional vitamin and mineral product/s were also counted under vitamins and minerals. FDC=Fixed-dose combination, NLEM=National List of Essential Medicines
Single drugs not included in the National List of Essential Medicines 2015 in any strength or dosage form
Levocetirizine was the most frequently prescribed single drug, included in 258 (5.33%) prescriptions [Table 3]. Famotidine (71 or 1.47% prescriptions) and proton-pump inhibitors (93 or 1.92%) were also frequently prescribed single drugs.
Table 3.
Most frequently prescribed single drugs products not included in the National List of Essential Medicines 2015 in any strength or dosage form
| Drug | Number of Prescriptions (percentage of n=4838), n (%) | Equivalent/alternative in NLEM 2015 | Number of prescriptions (percentage of n=4838), n (%) | Equivalent/alternative in WHO EML 2019 | Remarks/suggestions |
|---|---|---|---|---|---|
| Levocetirizine | 258 (5.33) | Cetirizine | 152 (3.14) | □Loratadine* | No advantage over cetirizine, more expensive[6,7] |
| Famotidine | 71 (1.47) | Ranitidine | 271 (5.60) | □Ranitidine | Can be considered for inclusion in NLEM[7,8] |
| Itraconazole | 53 (1.10) | Fluconazole | 21 (0.43) | Itraconazole | Can be considered for inclusion in NLEM[9,10,11] |
| Methylcobalamin | 49 (1.01) | Hydroxocobalamin | 36 (0.74) | Hydroxocobalamin | May be inferior/nonsuperior to Hydroxocobalamin[12] |
| Drotaverine | 46 (0.95) | Nil† | - | Nil | Therapeutic role not well established[13] |
| Losartan | 43 (0.89) | Telmisartan | 49 (1.01) | □Losartan | Lesser efficacy compared to telmisartan14,15 |
| Esomeprazole | 40 (0.83) | Omeprazole | 187 (3.87) | □Omeprazole | No advantage over omeprazole[8,16,17] |
| Rabeprazole | 38 (0.79) | ||||
| Olanzapine | 35 (0.72) | Risperidone, clozapine | 38 (0.79) 4 (0.08) | Risperidone, clozapine (complementary list) | Subject expert opinion required |
| Vildagliptin | 33 (0.68) | Metformin, glimepiride | 289 (5.97) 113 (2.34) | Metformin, □Gliclazide | Subject expert opinion required |
| Dextromethorphan | 33 (0.68) | Nil | Nil‡ | Doubtful efficacy, risk of adverse effects and abuse[18] | |
| Total | 699 (14.45) | 1156 (23.89) |
*The square box symbol (□) indicates similar clinical performance within a pharmacological class. †No phosphodiesterase 4 inhibitor is listed in NLEM 2015 or WHO EML 2019. ‡No antitussive is listed in NLEM 2015 or WHO EML 2019. Codeine is listed in WHO EML 2019 as an analgesic. NLEM=National List of Essential Medicines, EML=Essential Medicines List, WHO=World Health Organization
Single drugs included in the National List of Essential Medicines 2015 in a different strength or dosage form
Pantoprazole was the most commonly used drug in a dosage form other than NLEM. Tablet/capsule pantoprazole 40 mg was prescribed in 249 (5.15%) prescriptions, while NLEM 2015 includes only injection pantoprazole 40 mg [Table 4].
Table 4.
Most frequently prescribed single drug products included in the National List of Essential Medicines 2015 in a dosage form or strength other than that prescribed
| Drug | Product | Number of prescriptions (percentage of n=4838), n (%) | Dosage form or strength listed in NLEM |
|---|---|---|---|
| Pantoprazole | Tablet 40 mg | 249 (5.16) | Injection 40 mg |
| Cholecalciferol | Oral liquid 60,000 IU/5 mL; granules | 70 (1.45) | Tablet 1000 IU, tablet 60,000 IU, oral liquid 400 IU/mL |
| Diclofenac | Gel/ointment/spray; tablet 75 mg | 65* (1.35) | Tablet 50 mg/injection 25 mg/mL |
| Total | 384 (7.94) |
*Four tablets and the rest topical products. NLEM=National List of Essential Medicines
Fixed-dose combinations
For the majority of non-NLEM FDCs (214 or 60.45% of non-NLEM FDCs) prescribed, one or more (but not all) components were listed in the NLEM as separate drugs [Table 5].
Table 5.
Most frequently prescribed fixed-dose combinations which are not included in the National List of Essential Medicines 2015
| Number of prescriptions (percentage of n=4838), n (%) | |
|---|---|
| FDCs in which no component is included in NLEM | |
| Montelukast + levocetirizine | 48 (0.99) |
| Aluminum hydroxide + magnesium hydroxide + oxetacaine | 45 (0.93) |
| Pregabalin + MeCbl | 32 (0.66) |
| Bacitracin + neomycin + polymyxin B | 25 (0.52) |
| Trypsin + chymotrypsin | 24 (0.50) |
| Pregabalin + nortriptyline | 24 (0.50) |
| Total | 198 (4.09) |
| FDCs in which one or more component is included in NLEM | |
| Multivitamins with or without minerals | 842 (17.40) |
| Domperidone + rabeprazole | 74 (1.53) |
| Ceftriaxone + sulbactam | 49 (1.01) |
| Pantoprazole + domperidone | 47 (0.97) |
| Total | 1012 (20.92) |
| FDCs in which all components are included in NLEM but as separate drugs | |
| Ibuprofen + paracetamol | 39 (0.81) |
| Acetylsalicylic acid + atorvastatin | 38 (0.79) |
| Mefenamic acid + dicyclomine | 37 (0.76) |
| Diclofenac + paracetamol | 15 (0.31) |
| Total | 129 (2.67) |
| Grand total | 1339 (27.67) |
MeCbl=Methylcobalamin, NLEM=National List of Essential Medicines, FDC=Fixed-dose combination
Among the FDCs for which none of the components were included in NLEM, montelukast + levocetirizine was the most frequently prescribed (48 or 0.99% prescriptions). Aluminum and magnesium hydroxide-containing FDCs were prescribed in 64 prescriptions, the most common being aluminum hydroxide + magnesium hydroxide + oxetacaine (46 or 0.95% prescriptions). Pregabalin with methylcobalamin was prescribed in 32 (0.66%) prescriptions, while pregabalin was combined with nortriptyline in 24 (0.5%) prescriptions. An FDC of trypsin + chymotrypsin was prescribed in 24 (0.50%) prescriptions. Trypsin and/or chymotrypsin were also part of additional five FDCs (25 prescriptions). Another proteolytic drug, serratiopeptidase, was prescribed as a single drug in 12 prescriptions and as a component of 4 different FDCs in 57 (1.18%) prescriptions.
Among the FDCs with at least one component included in NLEM, vitamin and mineral preparations were the most common, with 91 different FDCs prescribed in 842 (17.40%) prescriptions. At least one Vitamin B (other than folic acid and Vitamin B12) was a component of 61 of these FDCs, prescribed in 419 (8.66%) prescriptions. Folic acid, Vitamin B12, and iron were components of 84 FDCs prescribed in 356 (7.36%) prescriptions. Of these, 39 FDCs were anti-anemia preparations (172 prescriptions) while the remaining were prescribed as supplements along with other vitamins and/or minerals. Vitamin B12 was a component of 40 FDCs prescribed in 161 prescriptions, mostly as methylcobalamin (32 FDCs in 110 prescriptions). A total of 330 prescriptions included one of 28 different calcium-containing FDCs (excluding FDCs containing calcium dobesilate and calcium pantothenate).
Domperidone plus rabeprazole (74 prescriptions) and pantoprazole (47 prescriptions) were also frequently prescribed FDCs. Only domperidone is included in NLEM 2015. A total of five FDCs contained a PPI plus domperidone (141, or 2.91% prescriptions) and another five FDCs combined a PPI with another prokinetic (35 prescriptions).
Ibuprofen plus paracetamol was the most prescribed FDC for which all components are included in NLEM 2015 separately (39 or 0.81% prescriptions). Nonsteroidal anti-inflammatory medicines (NSAIMs) were a component of 35 non-NLEM FDCs prescribed in 381 (7.88%) prescriptions; 13 of these FDCs (prescribed in 176 prescriptions) contained paracetamol along with an NSAIM.
Discussion
Many studies have underscored the errors in prescribing performance of medical graduates, partly because of inadequate training.[6] Identification of these errors or gaps in prescribing is the first step in designing a training program in prescribing skills. One of these gaps is the underutilization of the EML.[7]
In our study, more than half (55.33%) of the prescriptions had at least one non-NLEM drug, amounting to 31.12% of total drugs prescribed. Drug utilization studies in India have found the percentage of non-NLEM drugs prescribed varying from 10% to 75%.[3,8] Studies from South and South East Asian countries, e.g., Bangladesh, have reported the prescription of non-EML drugs to be 20%–70%.[3] In Malaysia, a countrywide evaluation of outpatient encounters in PHCs reported 100% prescription from the EML, while another study found that only 33% of the 81 most frequently used medicines were from the EML.[3] Utilization of essential medicines was found to be high in public hospitals in Malaysia, where prescribers need to prescribe from the hospital supply.
Vitamin and mineral preparations were the most frequently prescribed non-NLEM drugs in our study, as 8 single drug products and 91 different FDCs. Prescribing of vitamins and minerals has low clinical priority and is only appropriate where there is a medically diagnosed deficiency. These are therefore not included in NLEM 2015, and their use to the extent encountered in our study is suggestive of overuse. The availability of a large number of vitamin and mineral FDCs in our country facilitates their misuse, and these are often prescribed without scientific rationale.[9,10]
A majority of the Vitamin B12 FDCs contained methylcobalamin (MeCbl), which was also one of the frequently prescribed single drugs (49, or 1.01% prescriptions). Hydroxocobalamin is the Vitamin B12 form in NLEM 2015, but there were only 36 prescriptions of hydroxocobalamin. These were all from one center, where methylcobalamin was dispensed since hydroxocobalamin was not available. We were not able to find any oral preparation of hydroxocobalamin in India, either online, in physical drug references or at hospital or local pharmacies. Only injection hydroxocobalamin and FDCs of hydroxocobalamin appear to be available in India, despite oral hydroxocobalamin being listed in our NLEM. MeCbl is easily available but may not reverse the neurological deficit due to vitamin B12 deficiency, although it may be noninferior to cyanocobalamin (CNCbl) in patients with diabetic neuropathy.[11] Till there is more evidence of interchangeability of the various forms of Vitamin B12, it may be prudent to treat Vitamin B12 deficiency with hydroxocobalamin or cyanocobalamin or a combination of MeCbl and adenosylcobalamin.[11] However, the nonavailability of hydroxocobalamin in the Indian market makes it impossible for it to be prescribed and utilized.
Levocetirizine was the most frequently prescribed (258 or 5.33% prescriptions) second-generation antihistamine, although cetirizine is listed in NLEM 2015. Cetirizine was prescribed in only 152 (3.14%) prescriptions. Although levocetirizine is less sedating than first-generation antihistamines, its sedative effects are similar to cetirizine.[12] In addition, levocetirizine is more expensive than cetirizine, with a price range of Indian rupees (INR) 23.8–65 per ten 5 mg tablets for levocetirizine and INR 2.3–40.38 for 10 tablets of cetirizine 10 mg (cetirizine 10 mg is equivalent to levocetirizine 5 mg).[13] Therefore, the use of levocetirizine instead of cetirizine does not seem to be justified. Another important finding was the use of the FDC levocetirizine + montelukast (48 prescriptions). Although montelukast may be appropriate for patients unwilling or unable to use inhaled corticosteroids, it has been associated with serious neuropsychiatric adverse effects, prompting the US Food and Drug Administration (FDA) to require a black box warning about its risk of serious mental health adverse drug effects.[14] Due care therefore is needed before prescribing montelukast.
Famotidine was another frequently prescribed non-NLEM drug, although it was prescribed much less frequently than ranitidine, which is the only histamine H2 receptor antagonist (H2RA) in NLEM 2015. There were only 71 (1.47%) prescriptions for famotidine, compared to 271 (5.60%) for ranitidine. Famotidine was deleted from NLEM 2011 which included both ranitidine and famotidine, as it was more expensive of the two. Although there is no evidence of any clinical benefit of famotidine over ranitidine, famotidine does have a slightly longer duration of action (10–12 h compared to 6–8 h for ranitidine) and a lesser tendency to cause drug-metabolizing cytochrome P450 (CYP450) inhibition[15] and the resultant drug-drug interactions. Furthermore, although famotidine was earlier more expensive than ranitidine, it is now less so, with a price range of INR 2.10–11.34 for 14 tablets of 20 mg (INR: 0.15–0.81 per tablet, available commonly in strips of 14) compared to INR 4.9–19 for 10 tablets (INR: 0.49–1.9 per tablet[13] of an equivalent strength of ranitidine 150 mg).
Non-NLEM PPIs (esomeprazole, rabeprazole, lansoprazole, and oral pantoprazole) were frequently prescribed (342 or 7.07% prescriptions), compared with only 187 (3.87%) prescriptions for omeprazole, which is the oral PPI in NLEM 2015. Although there are pharmacokinetic differences among the various PPIs,[8] affecting the speed of onset of action and duration of acid inhibition in the initial few days of treatment, they are of little clinical significance with continued daily administration, and the PPIs are comparable at equivalent doses with no advantage of one over the other.[15,16] Kinetic characteristics that could be irrelevant to the drug effectiveness, but stressed to promote an expensive drug, often lead to cheaper alternatives being underutilized.[17]
PPIs were also commonly prescribed as 10 different FDCs with a prokinetic (170 or 3.51% prescriptions), mostly domperidone (5 FDCs in 141 or 2.91% prescriptions). Although combination therapy with PPI and a prokinetic may be indicated in gastroesophageal reflux disease (GERD), the American College of Gastroenterology 2013 guideline recommends that therapy for GERD other than acid suppression, including prokinetic therapy, should not be used without diagnostic evaluation[18] and the evidence to support domperidone use in functional dyspepsia is of very low quality.[19] Availability of PPIs plus prokinetic FDCs encourages early use of the combination instead of a trial of PPIs alone first. This not only exposes patients to avoidable increase in cost of therapy but also puts them at risk of serious adverse drug reactions as domperidone may cause QT prolongation and arrhythmias. Even if domperidone is indicated as an antiemetic in functional dyspepsia, an FDC is not rational as peptic ulcer is not always associated with vomiting.
Losartan was prescribed almost as frequently as its NLEM equivalent telmisartan (43 and 49 prescriptions as a single drug, respectively, and 17 and 25 prescriptions as FDC, respectively). Losartan was listed in NLEM 2011 but deleted and replaced with telmisartan in NLEM 2015, as the latter is superior to losartan 50/100 mg in controlling hypertension[20] as well as in reducing proteinuria in diabetic nephropathy.[21]
Drotaverine, a phosphodiesterase 4 inhibitor with anticholinergic effects, was prescribed in 46 (0.95%) prescriptions for abdominal pain or as an antispasmodic in urinary tract infection. It may be effective for postoperative urinary retention and irritable bowel syndrome but has not been approved by the US FDA. In India, drotaverine forms part of the programmed labor protocol and some studies claim it to be superior to other antispasmodics in labor.[22] However, the role of antispasmodics in labor is controversial and none of the antispasmodics, including drotaverine, are of clear benefit.[23]
Fluconazole is the only systemic azole antifungal in NLEM 2015. However, itraconazole has a broader spectrum of activity, being active against fungal infections such as blastomycosis, histoplasmosis, and aspergillosis, for which fluconazole is not effective.[24] Similarly, while the NLEM lists only insulin, glimepiride, and metformin as antidiabetic drugs, dipeptidyl peptidase-4 (DPP IV) inhibitors are recommended options for diabetic patients not controlled with metformin alone.[25] Besides vildagliptin, other gliptins encountered in our study as single drugs were teneligliptin, sitagliptin, and linagliptin (68 prescriptions). There were also four different FDCs of a gliptin with metformin (15 prescriptions).
Risperidone and clozapine are the only atypical antipsychotics listed in NLEM. However, we found olanzapine to be prescribed nearly as frequently as risperidone (35 prescriptions of olanzapine vs. 38 for risperidone.), while clozapine was prescribed in only 4 prescriptions. Limited use of clozapine was an expected finding, due to the life-threatening agranulocytosis associated with it. Olanzapine is an atypical antipsychotic, first approved by the US FDA in September 1996, for the treatment of schizophrenia. Several meta-analyses have established the efficacy and minimal extrapyramidal adverse effects with olanzapine compared to typical and some atypical antipsychotics, including risperidone, although, due to the risk of metabolic dysregulation and weight gain, most guidelines recommend olanzapine as a second-choice therapy for the treatment of schizophrenia.[26]
Dextromethorphan, another relatively frequently prescribed non-NLEM drug, is a centrally acting antitussive, through antagonism of NMDA (N-methyl-D-aspartate) and probably opioid receptors. Although it is commonly used for cough suppression, its efficacy is not significantly better than placebo, while it carries the risk of hallucinations and abuse potential.[27] No antitussive is listed in NLEM 2015 or WHO EML 2019. Codeine is listed in WHO EML only as an analgesic.
About half of the non-NLEM drugs, both in terms of different drug products used (51.12%) and total number of non-NLEM drugs prescribed (48.15%), were FDCs. Although FDCs are sometimes useful in potentiating the efficacy of component drugs, reducing adverse effects and antimicrobial resistance, improving medication adherence, and decreasing drug prices, there is a proliferation of FDCs in the Indian market which provide very few of these benefits.[28] NLEM 2015 includes only 24 FDCs out of 376 medicines.
Conclusion
Our study thus highlights the extent and pattern of prescription of drugs not included in NLEM 2015 at 13 tertiary health-care institutes across India, with more than half (55.33%) of the prescriptions including at least one non-NLEM drug, and nearly a third (31.12%) of the total drugs prescribed being from outside the NLEM. While we have not investigated the factors influencing this practice, we did come across the problem of nonavailability of an NLEM drug, i.e., hydroxocobalamin, which may be responsible for its underprescription. Furthermore, essential medicines are meant to cater to the health-care needs of the majority of the population, not all of the population. Therefore, especially at the tertiary care level, a certain volume of usage of drugs not included in an EML is to be expected. Another factor in the NLEM's underutilization is the prescriber's lack of knowledge about the NLEM and its role in making essential medicines accessible to all. Training and enhanced awareness among the prescribers may help bridge this gap between concept and practice. Some of the ways in which this can be carried forward are-
Training and education for prescribers
Training and education of medical graduates and prescribers needs to underscore:
Prescribing from the NLEM, such that non-NLEM drugs are only prescribed when there is a definite advantage of the prescribed drug over its NLEM alternative. For example, instead of levocetirizine and newer oral PPIs, prescribers need to be encouraged to use their NLEM equivalents, that is, cetirizine and omeprazole, respectively.
Restricted prescription of irrational FDCs, using the lists of banned FDCs (available from https://cdsco.gov.in) as a guidance.
Drugs which could be considered for inclusion in the National List of Essential Medicines
Itraconazole for fungal infections: Fluconazole is the only systemic azole antifungal in NLEM 2015. Itraconazole has a broader spectrum of activity, being active against fungal infections such as aspergillosis for which fluconazole is not effective,[24] and which is becoming increasingly prevalent in India.[29] Moreover, there has been an increase in the burden of dermatophytosis in recent years, for which terbinafine and itraconazole are recommended as systemic antifungals by the Indian Expert Forum Consensus Group.[30] Itraconazole is listed in the WHO EML 2019. Keeping above points in view, and in consultation with subject experts, itraconazole may be considered for inclusion in the revised version of the NLEM
Famotidine was deleted from NLEM 2011 which included both ranitidine and famotidine, as it was more expensive of the two. Although there is no evidence of any clinical benefit of famotidine over ranitidine, famotidine does have a lesser tendency to cause drug-drug-drug interactions.[15] Furthermore, although famotidine was earlier more expensive than ranitidine, it is now less costly. It may therefore be considered for inclusion in a revised version of NLEM, in lieu of ranitidine
Subject expert groups may be formed to consider the inclusion of the antipsychotic olanzapine and a gliptin antidiabetic in the revised NLEM at the tertiary health-care level.
Limitations
Although the study target was 600 prescriptions each from 13 tertiary health-care centers, with a total of 7800 prescriptions, we could capture and analyze only 4838 prescriptions, as due to the COVID-19 pandemic, many OPDs were closed for several months and only about 10% of the prescriptions (471) could be captured during the pandemic. Furthermore, only prescriptions from consenting patients and those with symptoms and a provisional diagnosis were included in the study, such that the prescriptions included may not be truly representative of prescribing practices at a tertiary health-care institute.
Financial support and sponsorship
Indian Council of Medical Research (ICMR) through its Task Force Project on Rational Use of Medicines
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
The authors are grateful to the Indian Council of Medical Research for support and funding of the ICMR-RUMC Network. We appreciate Dr. Ajay Shukla1, Dr. Ahmed Najmi1, Dr. Shubham Atal1, Dr. Avijit Hazra,4 and Dr. Rajiv Kumar5 for their valuable suggestions throughout the study. We also acknowledge Dr. Shakshi Singh1, Aarti Shrivastava1, Dr. Aakanksha Mathur,1 and Dr. Prakruti Patel2 for overseeing data collection of their respective centers; Saman Pathan1, Sateesh Meena1, Ranu Shakya1, Lata Pancholi3, Dr. Shilpa Hirani6, Dr. Sushmita Banerjee6, Dr. Badal Suthar6, Dr. Suchi Patel6, Dr. Krishna Limbani6, Dr. Dhara Naik6, Dr. Nilesh Dewan6, Dr. Dhruv Modi,6 and Pramila Manna4 for assisting in data collection and cleaning.
1AIIMS, Bhopal; 2BJMC, Ahmedabad; 3CMC, Ludhiana; 4IPGMER, Kolkata; 5IGIMS, Patna; 6Medical College, Baroda.
Annexure
Annexure I.
List of participating centers under the Indian Council of Medical Research Task Force Project on Rational Use Of Medicines
| RUMC | Number of prescriptions | Principal investigator |
|---|---|---|
| CMC, Vellore | 678 | Dr. Sujith Chandy sjchandy@gmail.com |
| VMMC, New Delhi |
605 | Dr. Preeta Kaur Chugh docpreeta@yahoo.com |
| CMC, Ludhiana |
600 | Dr. Dinesh Badyal dineshbadyal@gmail.com |
| AIIMS, Bhopal |
599 | Dr. Balakrishnan S head.pharm@aiimsbhopal.edu.in |
| PGIMER, Chandigarh |
557 | Dr. Bikash Medhi drbikashmedhi@gmail.com |
| SGSMC and KEM, Mumbai |
479 | Dr. Sandhya Kamat drsandhyakmat@gmail.com |
| IGIMS, Patna | 348 | Dr. Harihar Dikshit dikshithariharpatna@yahoo.co.in |
| IPGMER, Kolkata |
300 | Dr. Suparna Chatterjee drsupchat@gmail.com |
| MC, Baroda | 300 | Dr. Niyati Trivedi natrivedi@yahoo.com |
| BJMC, Ahmedabad |
102 | Dr. Chetna Desai chetna99@gmail.com |
| AIIMS, New Delhi |
100 | Dr. Pooja Gupta drgupta.pooja@gmail.com |
| JIPMER, Puducherry |
100 | Dr. Raveendran R dr.ravee@gmail.com |
| DMCH, Ludhiana |
70 | Dr. Sandeep Kaushal skaushal1@gmail.com |
| STM, Kolkata | - | Dr. Santanu K Tripathi tripathi.santanu@gmail.com |
RUMC=Rational Use of Medicines Centres, MC=Medical College, CMC=Christian MC, VMMC=Vardhman Mahavir MC, AIIMS=All India Institute of Medical Sciences, PGIMER=Postgraduate Institute of Medical Education and Research, SGSMC and KEM=Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, IGIMS=Indira Gandhi Institute of Medical Sciences, IPGMER=Institute of Postgraduate Medical Education and Research, BJMC=B J Medical College, JIPMER=Jawaharlal Institute of Postgraduate Medical Education and Research, DMCH=Dayanand MC and Hospital, STM=School of Tropical Medicine, SJMC=St John‘s MC
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