Current General Studies Magazine (August 2014)
General Studies - III (Science And Technology based Article)
Fixed Dose drug Combinations (FDCs)
Combination products, also known as fixed dose drug
combinations (FDCs), are combinations of two or more active drugs in a single
dosage form. The Food and Drug Administration, USA defines a combination product
as ‘a product composed of any combination of a drug and a device or a biological
product and a device or a drug and a biological product or a drug, device, and a
biological product. It is widely accepted that most drugs should be formulated
as single compounds. Fixed ratio combination products are acceptable only when
the dosage of each ingredient meets the requirement of a defined population
group and when the combination has a proven advantage over single compounds
administered separately in therapeutic effect, safety or compliance . FDCs are
highly popular in the Indian pharmaceutical market and have been particularly
flourishing in the last few years.
The rationality of FDCs should be based on certain aspects such as :
- The drugs in the combination should act by different mechanisms.
- The pharmacokinetics must not be widely different.
- The combination should not have supra-additive toxicity of the
Most FDCs have the following merits:
In addition to simply being a means of facilitating the general advantages of
combination therapy, specific advantages of fixed-dose combination (FDC) drug
Improved medication compliance by reducing the pill
burden of patients. Note that pill burden is not only the number of pills
needing to be taken, but also the associated burdens such as keeping track
of several medications, understanding their various instructions, etc.
Ability to compose combined profiles of for example
pharmacokinetics, effects and adverse effects that may be specific for the
relative dosages in a given FDC product, providing a simpler overview
compared to when looking at the profiles of each single drug individually.
Such a combined profile can also include effects caused by interaction
between the individual drugs that may be omitted in individual drug
Since FDCs are reviewed by regulating agencies (such as
the Food and Drug Administration in the United States), the active
ingredients used in the FDCs are unlikely to exhibit adverse drug
interactions with each other. However, FDCs may interact with other drugs
that a patient is taking, so the usual medical and pharmaceutical
precautions against drug-drug interactions or DDIs remain warranted.
FDC drug products may be developed by a pharmaceutical
company as a way to in effect extend proprietary rights and marketability of
a drug product. Since FDCs may be protected by patents, a company may obtain
exclusive rights to sell a particular FDC or formulation thereof, even
though the individual active ingredients and many therapeutic uses thereof
may be off-patent.
Most FDCs have the following demerits:
- Dosage alteration of one drug is not possible without alteration of the
- Differing pharmacokinetics of constituent drugs pose the problem of
frequency of administration of the formulation.
- By simple logic there are increased chances of adverse drug effects and
drug interactions compared with both drugs given individually.
The recent 14th model list of essential drugs prepared by the
WHO (March 2005) includes 312 formulation of which 18 are fixed dose drug
combinations . The World Health Organization's (WHO) Model list of Essential
Drugs provides examples of some rational FDCs such as :
- sulfamethoxazole + trimethoprim
- antitubercular FDCs like rifampicin + isoniazid, isoniazid + ethambutol,
- antiparkinsonism FDCs like levodopa + carbidopa
Unfortunately, many FDCs being introduced in India are
usually irrational. The most pressing concern with irrational FDCs is that they
expose patients to unnecessary risk of adverse drug reactions, for instance,
paediatric formulations of nimesulide + paracetamol. Nimesulide alone is more
antipyretic than paracetamol, more anti-inflammatory than aspirin, and
equivalent in analgesia to any of the NSAIDS alone , so efficacy gains are
unlikely with added paracetamol. However, the patients may be subject to
increased hepatotoxic effects from the combination. FDCs of diclofenac +
serratopeptidase do not offer any particular advantage over the individual drugs
despite the claim that serratopeptidase promotes more rapid resolution of
inflammation . On the other hand, the patient is exposed to greater risk of
gastrointestinal (GI) irritation and serious bleeding from unsuspected peptic
ulceration. FDCs of quinolones and nitroimidazoles (e.g. norfloxacin +
metronidazole, ciprofloxacin + tinidazole, ofloxacin + ornidazole) have not been
recommended in any standard books , but continue to be heavily prescribed drugs
in GI infections, pelvic inflammatory disease, dental infection, etc., to cover
up for diagnostic imprecision and the lack of access to laboratory facilities.
Such injudicious use of antibiotic FDCs can rapidly give rise to resistant
strains of organisms, which is a matter of serious concern to the health care
situation in our resource poor country. A glaring example is the emergence of
ciprofloxacin-resistant Salmonella typhi strains which have made treatment of
typhoid fever a difficult and expensive proposition in India today .
In India, a variety of NSAID combinations are available,
often as over the counter products . These combinations are an easy way to sell
two drugs when one (or even none) may be needed for the patient. The ‘combined’
pills are marketed with slogans like ‘ibuprofen for pain and paracetamol for
fever’ and ‘ibuprofen for peripheral action and paracetamol for central action’.
It is indeed very unfortunate that the medical fraternity in India has fallen
prey to such gimmicks. The gullible patient then has to pay for the doctor's
complacence in terms of extra cost and extra adverse effects. There is no
synergism when two drugs acting on the same enzyme are combined. Thus combining
two NSAIDs does not and cannot improve the efficacy of treatment. It only adds
to the cost of therapy and more importantly, to the adverse effects and the
‘muscle relaxants’ in some of these combinations are of questionable efficacy.
Combinations of NSAIDS/analgesics with antispasmodic agents
are also available in India . They are not only irrational but also could be
dangerous. The antipyretic drug promotes sweating and thereby helps in heat
dissipation. On the other hand, the anticholinergic antispasmodic drug inhibits
sweating. Combining these two can result in dangerous elevation of the body
temperature . Some such fixed drug combinations are now banned in India .
Over the years the Indian Drug Control Authority has issued
banned notifications on many FDCs like analgin + pitofenone, vitamins B1 + B6 +
B12, cyproheptadine + lysine, etc. . But are these measures sufficient?
Obviously not, since these notifications have not deterred manufacturers from
coming out with new irrational FDCs. At this crucial juncture, when the global
community, represented by WHO, is making an all out effort to propagate the
concept of essential drugs amongst consumers throughout the world, our official
stance could be viewed as too meager. India, as the world's second most populous
country, should demand a more rational approach and not pay mere lip service to
the global campaign.
Irrational FDCs also impose unnecessary financial burden on
consumers. Medical practitioners who patronize such combinations could be the
centre of controversy when subjected to litigation in consumer forums, as these
combinations do not find mention in standard text or reference books and reputed
medical journals. Pharmaceutical manufacturers, however, continue to reap the
benefits of huge sales, and therefore continue to promote combinations with
The time has come for all practitioners and consumers to raise this matter
vociferously through all possible avenues. Drug regulatory bodies should take
urgent action to mitigate the free flow of irrational FDCs.
Source - US National Library of Medicine National Institutes of Health
What do you understand by Fixed Dose drug Combinations (FDCs)? Discuss
their merits and demerits. (200 words)
Discuss development in the areas of Fixed Dose drug Combinations (FDCs)
in context of India. (200 words)