Fixed dose combination
- 1. FIXED DOSE COMBINATION BY: PRIYA NIGAM M.Sc. Clinical Research
- 2. DEFINITION OF FDC The combination of two different drugs in a single pharmaceutical formulation is known as fixed drug dose combination. Medicines are an integral part of healthcare. More than one drug is frequently used for treatment of either single ailment or multiple comorbid conditions. Sometimes, two or more drugs are combined in a fixed ratio into a single dosage form, which is termed as fixed dose combinations (FDCs). The FDCs are justified when they demonstrate clear benefits in terms of (a) potentiating the therapeutic efficacy, (b) reducing the incidence of adverse effect of drugs, (c) having pharmacokinetic advantage.
- 3. Safety and efficacy • There is little question that many patients benefit from receiving more than one pharmaceutical active to treat a medical condition when their actions are synergistic, or at least additive. • Often, efficacy can be significantly improved with minimal impact on the combination product’s safety and tolerability. • The combination of a beta-blocker with a diuretic has a well-established safety and efficacy profile as an antihypertensive. • Raise the dose of the beta-blocker, and you start to have tolerability and safety issues, yet the diuretic alone has limited efficacy by itself. • Put them together, and you have a much better balance of efficacy and safety.
- 4. AS A RULE • Two drugs to be combined have approxiamately equal plasma half life • The ratio of doses of each component should depend on apparent volume of distribution and plasma concentration. • EXAMPLE: • Amoxycillin(t½ -1-2hr, Vd-0.21L/kg) hence clavulanic acid(t½-1-1.5hr, Vd- 0.2L/kg) hence these can be combined in their standard dose regimen.. i.e amoxycillin 500mg +clavulanic acid 125mg can be administered as 1 to 2 tablet 8 hourly
- 5. MERITS Convenience in dose schedule and better patients compiliance. Enchanced effect of the combination e.g-oestrogen+progestrogene Minimisation of side effects e.g- levodopa+carbidopa Reduction in number of pills improve the patient compilance.
- 6. DEMERITS • The do of any component cannot be adjusted independently. • Pharmacokinetics must not be widely different • It becomes difficult to identify one particular drug which is causing harmful/beneficial effects. • Some fixed dose combination show more adverse effect e.g- nimesulide+pcm
- 7. CONT.... • One of the drugs in the combination maybe wasteful e.g- vitamin+iron • There willl be increase in price if unnecessary drugs are include. e.g- ibf+pcm+caffeine • In FDC there is always a chance that individual medicines may not be present n adequate amt. e.g- multivitamins
- 8. RATIONAL FIXED DOSE COMBINATION • Improved patient compilance-simplified disease management for chronic diseases like HIV,diabetes,hypertension,asthma,etc • Better efficiacy-synergistic mechanism,improved ADME and drug resistance.
- 9. EXAMPLE OF RATIONAL COMBINATION • Amoxycillin+clavulanic acid • Ampicillin+sulbactam • Ferrous salt+folic acid • Levodopa+carbidopa • Lamivudine+zidovudine • Abacavir+lamivudine+zidovudine
- 10. IRRATIONAL THERAPY RESULT IN- • Adverse drug reactions • Emergence of resistant micro-organisms • Financial complications more costly • Masking/confusion/delyaing the correct digonsis
- 11. REASON FOR IRRATIONAL USE OF DRUGS 1. Faulty & inadequate training & education of medical graduates 2. Lack of diagonstic facilities/uncertainty of diagonsis 3. Lack of information related to indications & safety of drugs. 4. Poor communication between health professional & patient
- 12. CONT.. 5.Demand from the patient 6.Promotional activites of pharmaceutical industries 7.Defective drug supply system & infective drug regulation.
- 13. HAZARDS OF IRRATIONAL USE OF DRUGS • Irrational use of drugs may lead to: Ineffective & unsafe treatment Exacerbation or prolongation of illness Distress & harm to patient Increase the cost of treatment
- 14. EXAMPLES OF IRRATIONAL DRUG THERAPY Nimesulide+pcm- • FDC of analgesi, anti inflammatory and antipyretic results in increased hepatotoxicity Ampicillin+cloxacillin- • ampicillin is effective against Gram negative bacilli but Cloxacillin is an anti- staphylococcal penicillin and not effective againt Gram -ve and Staphylococcal(Gram +ve) infection rarely coexists.
- 15. CONT.. Gastrointestinal drugs- such as domperidone+rabeprazol increased incidence of rhabdomyolysis Anta acid+ antianxiety drug- the acid disease is rearly associated with pstchosomatic basis so, there is no justification of combining antianxiety drug with antacid Metformin+glimepiride+pioglitazone metformin is indicated drug in obese type-2 diabetes mellitus whereas Sulfonylurea(glimepiride) is indicated drug in non-obese type-2 diabetes mellitus.
- 16. FDC PRODUCTS 1990 TO 2013, CURRENT SITUATION • For the period 1990 through 2013, the FDA approved a total of 131 prescription FDC products. This amounts to an average of 5.5 FDC products per year. The peak year for FDA approvals was 2012, with 12 FDC products approved. The low point was 1991 when only a single FDC product was approved. Figure 1 provides a summary of approvals by year. • Of the 131 approved prescription FDC products approved in this period, a total of 13 have been discontinued. In some cases, the products were withdrawn because of poor commercial performance, while in other cases, the products were superseded by improved presentations. Two active FDC products accounted for 117 of the FDC products, while there were 12 products with three actives and only 2 with four actives. • Digging a little deeper, we find that for 21 of the 131 FDC products, the approval of the FDC product was the first approval for at least one the actives. In one case, Courted (Application Number 22268), the FDC product approval represented the first approval for both of the actives in the product.
- 17. CONCLUSION • According to the WHO Expert Committee, combination drugs should be only used when there are no alternative of single drugs available or cost effective for the purpose. • Combination drugs increase the risk of side effects and may also needlessly increase the cost. • Combination drugs are irrational also because their stability is dpubtful, reducing the efficacy of many preparations.
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