ejbps, 2015, Volume 2, Issue 5, 429-439.
Dhande et al.
Research Article
SJIF Impact Factor 2.062
ISSN 2349-8870 European Journal of Biomedical and Pharmaceutical Sciences European Journal of Biomedical Volume: 2 AND Issue: 5 429-439 Pharmaceutical sciences Year: 2015
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PRESCRIBING TREND OF FIXED DOSE COMBINATIONS (FDCs) IN A TERTIARY CARE TEACHING HOSPITAL IN WESTERN INDIA 1*
1
Priti Dhande, 2Hardik Patel and 3Amit Gupta
Associate Professor, Department(s) and Institution(s): (All authors) Department of
Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Pune, Maharashtra. India. 2 rd
3 Yr Resident, Department(s) and Institution(s): (All authors) Department of
Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Pune, Maharashtra. India. 3 st
1 Yr Resident, Department(s) and Institution(s): (All authors) Department of
Pharmacology, Bharati Vidyapeeth Deemed University Medical College, Pune, Maharashtra. India. Article Received on 22/07/2015
*Correspondence for
Article Revised on 15/08/2015
Article Accepted on 07/09/2015
ABSTRACT
Author
Background: Fixed dose combinations are highly popular in the
Priti Dhande
Indian pharmaceutical market and are particularly flourishing in the
Associate Professor,
last few years. Today FDCs are in several thousands and many of them
Department(s) and
have no therapeutic rationale. Aim: This study was planned to screen
Institution(s): (All authors) Department of
the prescriptions in the outpatient department of a tertiary care teaching
Pharmacology, Bharati
hospital to assess the status of prescribed FDCs. Methodology: This
Vidyapeeth Deemed
was a retrospective study conducted in the month of May 2013 in
University Medical College,
which OPD prescriptions were accessed from the hospital record
Pune, Maharashtra. India.
section for presence of FDCs. Results: We observed 193 FDCs in 400 prescriptions during our study of which the most prescriptions were
from medicine (32%) and dermatology (20%) departments. Only 5.38% FDCs were from the 18th list (2013) of essential medicines (EML) by the WHO. Anti-inflammatory (27%) and nutritional supplements (23%) comprised of 50% of the total FDCs. Out of the total 55% irrational FDCs, 12% FDCs were unapproved and 19 combinations of Paracetamol had higher than recommended dose. Conclusion: FDCs are being rampantly prescribed by the
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physicians and even marketed by pharmaceutical companies without following World Health Organization (WHO) guidelines for drug combinations. KEY WORDS: Fixed dose combinations, retrospective, prescriptions, unapproved FDCs. INTRODUCTION Formulations containing a fixed ratio of two or more drugs in combination are called fixed dose combinations (FDCs). Over the years, rationally designed FDCs have been seen to be advantageous in reducing the number of pills, having simplified packing, lesser dispensing time and lesser cost which indirectly improved patient’s adherence to the treatment. Improved compliance with FDCs have special significance in the treatment of chronic infectious diseases e.g tuberculosis, acquired immune deficiency syndrome which can prevent drug-resistant strains, treatment failure and a threat to public health.[1] But there also are many drawbacks of FDCs which include increase in the price of preparation if unnecessary drugs are included and also increased incidence of adverse effects with difficulty to identify the culprit medicine in the FDCs. Titration of drug dose for individual patient is also not possible and there is always a possibility that individual medicines may not be present in adequate amounts, e.g., multivitamins in FDCs.[1] The 18th essential medicines list of WHO has 374 essential medicines, including 25 FDCs[2] whereas the national list of essential medicines of India has 348 essential drugs, including 16 drug combinations.[3] Despite this information, large number of FDCs are being sold in India under more than 1000 brand names.[4] The past years have shown that Indian Drug Control Authority has prohibited the manufacture and sale of many FDCs like diazepam and diphenhydramine hydrochloride, vitamins B1 + B6 + B12, nalidixic acid with any antiamoebic including metronidazole, etc.Inspite of these regulatory steps, manufacturers kept coming out with new irrational FDCs in the drug market.Some FDCs are found licensed by State Licensing Authority (SLA) but not approved by Drug Controller General of India (DCGI)& still are available for prescribing to the patients.[5] Many doctors, both in government as well as private setup are prescribing irrational FDCs with excuse of better patient compliance.[6] Pan et al compared a FDC to a 2pill regimen and concluded that the FDC enhanced adherence rates by approximately 13% when compared to a 2-pill regimen.[7] Pharmaceutical manufacturers, on the other hand, continue to enjoy the benefits of huge sales and hence continue to promote such combinations with more vigour.[8]
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The above-mentioned magnitude of the problem of prescribing irrational FDCs can be reduced by emphasizing the principles of rational drug use selection. Hence this study was planned to screen the prescriptions in the outpatient department (OPD) of a tertiary care teaching hospital to assess the status of prescribed FDCs. METHODOLOGY This was a retrospective study conducted in the outpatient department of a tertiary care teaching hospital in western India. Institutional Ethics Committee approval and Hospital superintendent’s permission was taken before commencement of the study. OPD records from the month of May 2013 were accessed from the hospital record section to obtain the following details from the OPD papers: Clinical department’s name; Patient’s age, gender, health problems and diagnosis ; FDCs prescribed with formulation, dosage and duration. The names of the prescribing doctors were kept confidential throughout the study. All these details about FDCs were collected and entered in the data collection form. Additional information like content / drugs of the FDC, its pharmacological class and its inclusion in the18thessential medicine list of WHO was collected.These FDCs were then grouped under the following categories:1) Rational FDCs- included in WHO essential drugs lists and also those which are pharmacologically correct in combinations. The rationality of these FDCs was determined by reviewing the available literature about the drug combination. 2) Irrational FDCs- if they did not follow the accepted rules for drugs in combination (Seven point criteria developed by Panda et al[2] for evaluating rationality of FDCs:
Each active pharmaceutical ingredient (API) of the combination should preferably be in the ‘essential medicines list’ (EML) of WHO or in the National List of Essential Medicines (NLEM) of India.
The dose of each API should meet the requirements for a defined population group. The dose and proportion of each API present in FDC should be appropriate for the intended use.
The combination should have the advantage of established evidence of efficacy and safety.
The overall cost of the combination should preferably be less than the cost of the individual components.
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The FDC should facilitate either the reduction ofthe dose of individual drugs or their adverse effects.
There should be no unfavourable pharmacokinetic interaction between the APIs.
The individual drugs should have different mechanism of action.
3) FDCs licensed by the SLA but not approved by DCGI 4) FDCs of Non steroidal anti-inflammatory drugs with improper dose of paracetamol (>325mg) were also considered irrational. STATISTICAL ANALYSIS: Data was entered in Microsoft Excel and analyzed to find out the percentage of different pharmacological classes of fixed dose combinations andtheir formulations. The obtained data was also analyzed for number of rational and irrational FDCs found in the study prescriptions. All these results are expressed as numbers or frequencies. RESULTS Total 400 prescriptions issued in the month of May 2013 were found in various outpatient departments of the tertiary care hospital. Among these 400 prescriptions, FDCs were present in 193 (48.25%) prescriptions. There was no gender difference seen among prescribing FDCs to the study population but the trend of prescribing FDCs seem to be rising with increasing age of the patients. Figure 1 shows various FDCs found in the study prescriptions. When analyzed for their content and pharmacological class, analgesics (27%), nutritional supplements (23%) and antimicrobials (11%) comprised of majority of the total FDCs analyzed in this study. Analgesic combinations included combination of two non-steroidal anti-inflammatory agents(NSAIDs) (paracetamol + NSAIDs), NSAID/s + muscle relaxant, NSAID/s + proteolytic enzymes, cold remedies containing paracetamol, opioid + paracetamol and topical gel / ointment preparations. Most common antimicrobial combinations prescribed were β lactam antibiotics + clavulanic acid and ciprofloxacin + tinidazole while the gastroprotective agents include proton pump inhibitor with a prokinetic agent. The various nutritional supplements found in the study prescriptions were hematinics, mutivitamins, herbal extracts and calcium preparations. Others category of FDCs (15%) included antihypertensives, antineuralgics, laxatives, antiplatelet agents, hypolipidemics, ear drops, etc. Skin protectants included aloe vera, vitamin E, calamine and other topical preparations.
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Figure 1: Pharmacological class of prescribed Fixed Dose Combinations (FDCs) (n = 193) Others- antihypertensives, anti-neuralgics, laxatives, antiplatelet agents, hypolipidemics, ear drops, etc.
Figure 2: Distribution of Fixed dose combination (FDC) formulations prescribed (n = 193) When studied for their formulations, tablets (62%) were the most common FDCs followed by topical preparations (21%) (Figure 2). Variety of tablets formulations prescribed wereenteric coated, sustained release, instant release and film coated.Topical preparations included lotion, cream, gel, soap, ointment, shampoo & ear drops.
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Table 1: Characteristics of Fixed dose combinations (FDCs) prescribed Characteristic of FDC 1.
Rational FDCs Irrational FDCs
2.
No rationale for combination as per WHO FDCs licensed by SLA but not approved by DCGI FDCs containing high dose (> 325mg)paracetamol FDCs from WHO’s 18th Essential drug list
3.
Total number (%) n=193 87 (45%) 106 (54.9%) 62 23 19 7 (5.38%)
WHO- World Health Organization, SLA-State Legislative Assembly, DCGI- Drug Controller General, India When analyzed for their rationality, > 50% of the FDCs found in the study prescriptions were irrational. The irrational FDCs found in the study prescriptions were Ciprofloxacin & tinidazole, Esomeprazole & domperidone, Pantoprazole & domperidone, Multivitamin preparations (Vitamin B1+B2+B3+B6+B12+Calcium pantothenate), Paracetamol + other NSAID, Diclofenac / aceclofenac with serratiopeptidase / trypsin chymotrypsin and Iron preparations containing B complex vitamins and/zinc. Only 7 drug combinations out of the total 193 FDCs were from the WHO’s 18th Essential drug list. DISCUSSION Nearly 50% of prescriptions contained a FDC.The finding of increased FDC use with rising age might be because of more chances of co-morbid conditions in elderly patients and their need of multiple medications. Most of the FDCs were found in the prescriptions from the departments of medicine (32%) and dermatology (20%)(Figure 1). In another study done by Rayasam SP,[10] maximum FDCs were also from the department of medicine (25.59%), followed by surgery (15.47%) and Ear, Nose & Throat (ENT) department 13.69%. Prescribed FDCs in our study were belonged were analgesics, nutritional supplements and antimicrobials. Similar results were obtained by Kastury N et al (1999)[11] and Rayasam SP (2011)[11] in their studies where antimicrobials followed by analgesics and nutritional supplements constituted majority of the total drug combinations prescribed. Even a study conducted in a dental setting[12] mentions that majority of the drug combinations prescribed were antimicrobials followed by non steroidal anti-inflammatory drugs.
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As mentioned in the Table 1, only 5.38% FDCs were from the WHO’s 18th Essential Medicine List. Similar results were obtained in a study conducted by Poudel A et al in Nepal (2007),[13] where only 25 (7.2%) drug combinations out of 352 medicines intotal were listed in the 15th WHO model list of essential medicines. Only 45% FDCs were found to be rational amongst those studied in our study. These were amoxicillin / cefpodoximeproxetil + clavulanic acid, calcium carbonate + vitamin D3, chlorzoxazone + paracetamol, furosemide + amiloride, telmisartan + amlodipine / hydrochlorthiazide, levodopa + carbidopa, aspirin + clopidogrel, chlorpheniramine maleate + phenylephrine + paracetamol + anhydrous caffeine, diclofenac + thiocolchicoside, liquid paraffin + magnesium hydroxide emulsion, tramadol + paracetamol etc. All of these are termed rational as per the WHO guidelines like active pharmaceutical ingredients (APIs) with complementary mechanism of action, decreased occurrence of adverse drug reactions or toxicity or resistance for antimicrobial agents (AMA), increased efficacy of the combination, increased compliance of the drug therapy with decreased pill burden, decreased total cost of therapy and appropriate dose of each API. More than 50% of the FDCs were irrational when the seven point criteria developed by Panda et al was applied to them for evaluating their rationality. Following are the reasons for irrationality of drug combinations found in our study prescriptions which were categorized as irrational FDCs: 1. Ciprofloxacin & tinidazole- Though claimed to be broad spectrum, combining antiameobic with fluoroquinolone (antibacterial) is irrational because patient suffers only from one type of diarrhea. Using this combination adds to cost, adverse effects and may encourage resistance. 2. Esomeprazole
&
domperidone-
Irrationality
due
to
increased
incidence
of
rhabdomyolysis. 3. Pantoprazole & domperidone- Combination of Pantoprazole (PPI) with antiemetic drug (Domperidone) is an irrational drug combination as gastric acidity is not always associated with vomiting. Even in gastro-esophageal reflux disease (GERD), domperidone is less effective as compared to metoclopramide, so combining PPI with domperidone is considered an irrational choice. 4. Multivitamin preparations (Vitamin B1+B2+B3+B6+B12+Calcium
pantothenate)-
Vitamins B1, B6 and B12 in a FDC are banned as deficiencies of three vitamins never
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occur together. To avoid the ban, the other two ingredients were added by the manufacturers which is irrational. 5. Paracetamol + other NSAID- The combination of paracetamol with NSAIDs may provide more effective analgesia for some patients, e.g. for post-surgical pain, than either medicine alone. However, this approach does not appear to be effective for all conditions. 6. Diclofenac / aceclofenac with serratiopeptidase / trypsin chymotrypsin- Serratiopeptidase, trypsin, chymotrypsin are proteolytic enzymes supposed to relieve inflammation. This claim is not based on controlled clinical trials and FDCs containing these compounds offer no additional anti-inflammatory advantage but higher cost to the patient. 7. Iron preparations containing zinc- Zinc is known to interfere with the absorption of iron; excess zinc in pregnant women is known to increase premature delivery and stillbirth, hence this combination is irrational. Combination of paracetamol with other NSAIDs for analgesia has been a controversial issue. One systematic review[14] found that such a combination was superior to paracetamol alone; but evidence of the better analgesic effect of this combination over NSAID alone is lacking. In our study, most of these combinations (32) were prescribed for non-surgical pain which render them irrational here.In January 2011, the U.S. Food and Drug Administration (USFDA) had asked manufacturers of prescription combination products that contain acetaminophen (paracetamol) to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule.[15] The manufacturers were also required to updatethe labels containing combination of acetaminophen products to warn of the potential risk for severe liver injury with the 500 mg dose combination products of paracetamol when used in more than prescribed dose. When we analyzed FDC preparations containing more than recommended dose of paracetamol, 19 FDCs of paracetamol with other drugs fell into this category (Table 1). Remaining 31 FDCs of paracetamol were in accordance with the USFDA recommendation containing 325 mg of paracetamol. On analyzing the haematinic iron preparations, it was found that all of them were irrational as they were combinations of iron and folic acid with B complex vitamin and/or zinc. On the recommendations made by the Drug Technical Advisory Board (DTAB), the Drug Controller General of India (DCGI) had directed the state drug authorities in 1999 not to allow the manufacture of iron preparations containing zinc, amino acids and vitamins other than folic acid and vitamin C from August 31, 2000.[16]
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When analyzed for their approved, unapproved / banned status, none of the banned FDCs were seen prescribed among the total 193 FDCs studied. 23 FDCs were such that they were licensed by State Legislative assembly (SLA) but not approved by DCGI(as shown in Table 1) like diclofenac / aceclofenac +paracetamol+serratiopeptidase; aspirin + atorvastatin; chlorzoxazone +paracetamol+ diclofenac sodium; domperidone maleate +paracetamol; pregabalin +mecobalamin, etc.Many irrational FDCs have been made available in the Indian market which may be due to the permission given by SLA. These approvals are illegal as any combination drug is considered to be a new drug under the Drugs and Cosmetics Act and its marketing approval has to be issued by DCGI only. The pharmaceutical companies have obtained product license for many irrational FDCs from SLA without the approval by DCGI for their efficacy and safety. Amongst the topical drug combinations,
8 FDCs contained corticosteroid with either
antimicrobial, antifungal or keratolytic agent, 4 prescriptions containing a combination of corticosteroid with gentamycin or mupirocin (2 each) and 2 prescriptions with a combination of corticosteroid+antifungal terbinafine were found. Combinations of steroid with an antimicrobial may be used for impetigo, furunculosis, secondary infected dermatoses, napkin rash, otitisexterna and intertrigenous eruptions. In our study, they were prescribed for eczema and reactive polyarthritis, 2 each, which is rationally justified. When topical corticosteroids are combined with potent antifungal drugs, they may interfere with the therapeutic action of the antifungal medications, thus exacerbating the infection.[17,18] Among the prescriptions studied, they were given for patients of lesions of lichen planus for which local corticosteroid formulation is indicated. Use of combination products of steroid with antifungal in this case is incorrect and should be discouraged as it is misuse of drugs and adds to the cost and adverse effects of the combination. The mushrooming of irrational FDCs in Indian market has posed a number of serious problems like ineffective dose of individual components,incompatible pharmacokinetics of the combined drugs,increased adverse effects, unnecessary use of combined drugs, increased costof medication and development of resistance with antimicrobial agents. These drawbacks are dreadful not onlyto the patients but also to the society in general. To overcome these risks due to irrational drug combinations,sensitization ofthe present day clinicians as well as the future practitioners (undergraduate[19] and postgraduate students) should be given utmost priority. Measures to improve rational prescribing should be www.ejbps.com
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strengthened in all possible ways- training sessions, efficient drug information centre, rational and logical thinking about using drug combinations etc. Unethical promotional activities by the manufacturers which influence the prescribers should be curtailed.Thus irrational FDCs should be kept under lens & banned from use. CONCLUSION FDCs are being rampantly prescribed by the physicians in a tertiary care set-up without giving consideration to its rationality. Inappropriate FDC use suggests an urgent need to sensitize the treating doctors about Essential medicine list, rationality, usage and banned FDCs. REFERENCES 1. Rational use of medicines. Good pharmacy practice - I.P.A.- C.D.S.C.O. - W.H.O. India country
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9. Panda J, Tiwari P, Uppal R, Evaluation of the rationality of some FDCs: Focus onantihypertensivedrugs.Indian J Pharm Sci, 2006; 68(5): 647-648. 10. Poudel A, Palaian S, Shankar PR, Jayasekera J, Izham MIM. Irrational fixed dose combinations in Nepal: Need for intervention. Kathmandu University Medical Journal 2008; 6(3): Issue 23, 399-405. 11. Rayasam SP, Dudhgaonkar SS, Dakhale GN, Hire RC, Deshmukh PS, Gaikwad NN. The irrational fixed dose combinations in the Indian drug market: an evaluation of prescribing pattern using WHO guidelines. Int J Basic ClinPharmacol 2013; 2 :452-7. 12. Kastury N, Singh S, Ansari KU. An audit of prescription for rational use of fixed dose drug combinations.Indian J Pharmacol.1999; 31: 367–9. 13. Sharma K, Sharma A, NeemawatK.An audit of prescription for rational use of fixed dose drug combinations at a tertiary care dental setting.Journal of Scientific and Innovative Research 2014; 3(5): 491-494. 14. Romsing J, Moiniche S and Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs for post-operative analgesia. British journal of Anaesthesia 2002; 88: 215-226. 15. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm(Acce ssed on 20.2.14) 16. Reynolds RD, Boiko S, Lucky AW. Exa-cerbation of tinea corporis during treatment with 1% clotrimazole/0.05% beta-methasone dipropionate (Lotrisone). American journal of diseases of children, 1991; 145(11): 1224–5. 17. Rosen T, ElewskiBE. Failure of clotrimazole-betamethasone dipropionate cream in treatment of Microsporumcanis infections. Journal of the American Academy of Dermatology, 1995; 32(6): 1050–1. 18. S.Srinivasan. Public Health Policy Making and Drug Industry: Issues in Knowledge Legitimation.
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