Abstract
Objective: To analyse the rationality of various FDCs used in the treatment of Diabetes Mellitus and to find out the irrational FDCs existing in the Indian market. Material and Methods: Study Design: Analytical study. Data on FDC's available in the Indian market was collected from Current Index of Medical Specialities (CIMS) and Monthly Index of Medical Specialities (MIMS) and their rationality was analysed using a pretested tool based on FDCs listed in WHO essential list of medicines and National List of Essential Medicines (NLEM), others based on their pharmacodynamic activity, Pharmacokinetic parameters and significant drug interactions occurring due to API (Active pharmaceutical ingredients) contained within the product Result: A total of 18 combinations were analysed, among those 11 combinations were irrational. Conclusion: Predominantly irrational FDCs are being circulated in the Indian market hence through analyses by prescribers is needed before prescribing to patients in order to avoid ADR. This calls for close scrutiny of marketed FDC's and educating prescribers to use them with great care and caution also indicates a serious review of the regulatory framework for drug manufacturing and marketing.
KEYWORDS: Fixed Dose Combinations; Antidiabetics; Irrational.
INTRODUCTION
Diabetes mellitus (DM), commonly referred to as diabetes is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period. Globally, an estimated 422 million adults are living with diabetes mellitus, according to the latest 2016 data from the World Health Organization (WHO) [1].
Fixed dose combinations (FDCs) refer to products containing two or more active drugs used in a single dosage form for a particular indication [2]. Prescribing Fixed Dose Combinations (FDCs) in Diabetes mellitus treatment is a routine practice. Although FDCs are associated with many advantages like synergistic action, reduced adverse effects, reduced pill burden, cost of the treatment and improved patients compliance [3] but certain disadvantages like incompatible pharmacokinetics, inflexible dose ratio and increased toxicity are limiting factors.
FDC is acceptable when the combination has proven advantage over single compound administered separately in terms of therapeutic efficacy or safety [4] Considering better patient compliance more and more physicians favour FDCs. As a result, pharmaceutical companies utilize this golden opportunity and market more and more combinations of which many of them are irrational.
Study Design: observational and Analytical study
Sample: Data on FDC’s available in the Indian market was collected from Current Index of Medical Specialities (CIMS) and Monthly Index of Medical Specialities (MIMS).
Analysis: All the quantitative variables have been expressed as mean and standard deviation and qualitative variables are expressed as percentages and proportions.
RESULTS
Total 18 FDCs were analysed. It was observed that 7 of the FDCs in antidiabetes drugs meet the criteria for rationality but there are 11 combinations found to be irrational.
Glibenclamide + metformin
Gliclazide + metformin
Glimipride +metformin
Glimipride + metformin + pioglitazone
Glipizide + metformin
Glibenclamide + metformin + pioglitazone
Glibenclamide + metformin + volgibose
Glimipride + metformin + Ramipril
Glimipride + metformin + Ramipril + atrovastatin
Glimipride + metformin + atrovastatin
Metformin + fenofibrinate
Figure 1. Shows the rational and irrational FDC
Figure 2. Shows percentages of different FDC’s used irrationally
DISCUSSION
Sulfonylureas + B iguanides :
Pharmacokinetics: After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively) [7].
Absorption of sulfoylureas is delayed by food and hyperglycemia
In view of time required to reach an optimal concentration in plasma, sulfonylureas are more effective when given 30min before food [8].
Antidiabetic + Antihypertensive + Hypolipidimics
A study conducted by Nisharan et. Al. showd that FDC when given in combination did not reach peak action of metformin, atrovastatin, and absorption of the metformin was reduced to only 80%, and delayed the absorbtion time which indicated the presence of interaction between these components [9].
They also violate some of the principles of formulation of FDCs like;
a. Increased efficacy in comparison to the individual components given at the same dose,
b. The incidence of adverse reactions in response to treatment with the combination is lower than in that in response to any of the component actives given alone,
c. Improved adherence, simplified therapy,
d. the actives in a combination should have similar pharmacokinetics. [10].
CONCLUSION
To conclude around 62% of the FDCs were found irrational. Indeed, it is very unfortunate and unethical to expose the innocent patients to medicines with unproven efficacy and safety. This calls for a close scrutiny of marketed FDCs and educating prescribers to use them with great care and caution. This also indicates a serious review of regulatory framework for drug manufacturing and marketing.
Financial Support and Sponsorship: Nil.
Conflicts of Interest: There are no conflicts of interest.
Acknowledgments: We are thankful to Department of Pharmacology, Shri B.M.Patil Medical College, Vijayapur for their guidance and help.
REFERENCES
- World Health Organization, Global Report on Diabetes. Geneva, 2016. Accessed 30 August 2016[http://www.who.int/diabetes/global-report/en/]
- Albert I, Wertheimer, Morrison A. Combination drugs: Innovation in Pharmacology. Pharmacol and Ther , 2002; 27(1): 46-49
- Gautam CS, Aditya S. Irrational drug combination: need for student sensitization. Ind J Pharmacol. 2006; 38(3):169-70
- Gautam C, Saha L. Fixed dose drug combinations (FDCs): rational or irrational: a view point. Br J Clin Pharmac. 2008; 65(5):795-796/795
- Shah S, Patel J, Desai M, Dikshit R. Critical analysis of antimicrobial and respiratory fixed dose combinations available in Indian market. International Journal of Medicine and Public Health. 2015; 5(2):161-164.
- Guidelines for registration of fixed-dose combination medicinal products. Geneva. World Health Organization 2005.Report number 929
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020496s021lbl.pdf
- Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In: Goodman and Gilman's the pharmacological basis of therapeutics, 12thedn, edsBrunton LL, Lazo JS, Parker KL New York: McGraw-Hill, 2011; 1255–1257.
- Ranpise N, Jamkar P, Langote H. Formulation and Development of Fixed Dose Combination of Antihypertensive and Antidiabetic Agent for treatment of Co-existent Type Two Diabetes Mellitus and Hypertension. Indian Journal of Pharmaceutical Education and Research. 2014;48 (supplementary):114–22.
- Guidelines on Fixed Dose Combinations (Fdc), Central Drugs Standard Control Organization India. April 2010 Page No 18 To 62 http://cdsco.nic.in