Fixed dose combinations (FDCs) are formulations containing two or more active drugs combined in a fixed ratio. FDCs are justified when they demonstrate benefits like improved therapeutic efficacy, reduced adverse effects, or pharmacokinetic advantages. Rational FDCs can improve compliance for chronic diseases and have better efficacy through synergistic mechanisms. However, irrational FDCs may cause adverse reactions, emergence of resistance, and financial burden. The benefits of FDCs must outweigh the risks like inability to adjust drug doses independently and difficulty identifying the cause of effects. Regulators generally approve FDCs only when alternative single drug options are not available or cost-effective.

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.

18. THANK YOU