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Pharma Voice
Fixed dose combinations in therapy
Avijit Chakraborti writes about the significance and
scrutiny of fixed dose combinations.
 The
basic aim of drug therapy is to treat a particular ailment with effective and
safe, good quality drugs. A large proportion of the drugs available, is of little
importance in terms of essential healthcare. It has become a very common practice
for physicians to prescribe more than one drug for a particular ailment. Whether
the physician prescribes multiple drugs because the fixed combination dosage
forms are easily available or the pharmaceutical manufacturers themselves make
these dosage forms, is a highly debatable issue. There are about 9,000 pharma
units and around 90,000 formulations in the country.
FDCs in the Indian scenario
More than one-third of all the new drug products introduced worldwide during
the last decade were fixed dose combination (FDC) preparations. The trend varied
from country to country. In Japan, only 10 percent of the new products were
fixed ration combinations, whereas, in European countries like Spain, it was
upto 56 percent. However, such statistical data are lacking for the developing
countries, although, the trend seems to be the production and prescription of
FDCs. The World Health Organisation (WHO) lists nearly 325 essential drugs,
including only 19 of such drug combinations. Whereas, the national list of essential
medicines has 354 essential drugs, including 14 drug combinations. FDCs available
for the treatment of various ailments range from nutritional deficiency to cardiovascular
diseases. Maximum FDC preparations comprise vitamins, cough suppressants, anti-diarrhoeal,
iron preparations, antacids, analgesics and tonics.
There are many popular FDCs in the Indian pharmaceutical market, which have
flourished in the last few years. Medical experts world over have been expressing
serious concerns over the marketing of increasing number of drug combinations
by pharmaceutical companies, particularly in the developing countries. Some
FDCs can impose unnecessary financial burden, increased adverse effects, as
well as hospitalisation, and decreased quality of life.
The Indian drug control authority has issued notifications banning many FDCs.
The principal notification under Section 26-A of the Drugs and Cosmetics Act,
1940, (prohibiting manufacture, sale and distribution of certain FDCs, which
do not have any therapeutic justification or are likely to involve risk to human
being) banned 79 drug formulations from the year 1983 till date. Some examples
are FDCs of vitamins with anti-inflammatory agents and tranquillisers, of anti-histamines
with anti-diarrhoeals etc.
The Drugs Controller General of India (DCGI) had given marketing approvals for
40 FDCs in January 2002. It is an accepted fact that an FDC be treated as a
new drug, because by combining two or more drugs, the safety, efficacy, and
bioavailability of the individual Active Pharmaceutical Ingredient (API) may
change. As per the Drugs and Cosmetic Act, 1940, any new drug and the permission
to market a drug is to be given by the DCGI. As per rule 122(E) of the Drugs
& Cosmetic Rules, 1945, the same criteria holds good for US markets as well.
WHO has made the following observations regarding the FDCs, as new fixed ratio
combination products are regarded as new drugs in their own right.
- The greater are the number of ingredients,
the less likely the prescriber or the physician is to know what FDCs
are and what are their adverse reactions. A combination makes it more
difficult to pinpoint the offending agent responsible for the adverse
reaction. This has been witnessed with analgesic mixtures in the past,
which contained phenacetin along with aspirin and caffeine (APC) Tablets.The
drug phenacetin has now been banned as it led to renal disease
- Another drawback with FDCs is that they
may lead to an ineffective dosage. In certain cases like heart failure,
it becomes necessary to determine the strength of the dose against the
appropriate end point. It is better to handle individual drugs rather
than combinations in such life threatening conditions
- Some FDCs are considered unsatisfactory
or undesirable. The present view is to restrict oral barbiturates to
patients with epilepsy. This is to reduce the risks of dependency, abuse
and attempted suicide, as well as to avoid induction of liver enzymes,
which renders concomitant therapy with corticosteriods, as well as other
drugs, less effective
- Some FDCs were banned as they were harmful
and caused problems instead of benefiting to the ailing patients.
- Some FDCs lead to abuse. For example,
drug dependence of dextropropoxyphene leads to accidental or intentional
over dosage and sometimes it is abused for suicidal attempts as well.
Patients using combination products often complicate overdose with Dextropropoxyphene
- Some FDCs when combined lead to increased
toxicity. For instance, the anti-TB drugs, streptomycin, kanamycin and
capremycin cannot be combined, as they have the same side effects (oto
and nephro-toxicity)
- If the biological half-life of different
compounds of a FDC are different, it may considerably affect the pattern
of drug availability in the plasma, and hence, the over all efficacy
of the preparation
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Corrective measures
The system of screening the drug combinations that are already licensed and
are moving in the market, is a new concept. This is being practised in many
developed and developing countries, including India, Although it may give rise
to questions regarding the drug combination's safety or rationality. To understand
this paradox, one must appreciate that no drug or chemical is absolutely safe.
Before the approval of any drugs, the Central Drugs Standard Control Organization
(CDSCO) undergoes a process with respect to their quality, safety and efficacy.
The DCGI monitors the drug formulations, including the combinations of drugs,
from the angle of safety, effectiveness and rationality. The role of Indian
Council of Medical Research (ICMR) may be explored with respect to new combinations,
as well as the guidelines of the USFDA, WHO and ICH may be followed to obtain
results.
With the assistance of WHO, the DCGI keeps a continuous monitoring of any drug
withdrawn in any other country (on the ground of lack of sufficient evidence
of its safety or effectiveness in context of present knowledge). If any such
drug or its combinations is marketed in the country, a decision to withdraw
the drug or its combinations from the market is taken care of by the pharmacovigilance
committee in the country. This committee, while giving their recommenda-tions,
invariably take into consideration the evidence of any reported adverse effect
of the drug indicated, the availability of safer and economic substitutes of
the drug or its combination and the benefit risk ratio.
The Drug Consultative Committee, a statutory body under the Drugs and Cosmetics
Act, had appointed a sub-committee of experts, who from time to time examine
formulations, including the combinations alleged at different forums (both national
and international) of being irrational or harmful or not effective in the context
of present knowledge.
This is a continuous process taking place in all the developed countries, through
which they can ban the harmful and irrational drugs and their combinations.
In India, once the recommendations by the drugs consultative committee are approved
by the drug technical advisory board (the highest technical body under Drugs
and Cosmetics Act), the government can take appropriate measures against such
formulations.
| A clinical need is of course an absolute requirement
for an FDC. The ingredients should all be necessary and should contribute
towards the therapeutic goal. Since the components are combined in one formulation,
the ingredients must be pharmaceutically compatible and their release and
bio-availability should be unimpaired even after combination. The dose range
of the constituents need to be narrow as the implicit individualisation
of dosage or flexibility is not required.
If the combination effect is more than that corresponding
to the sum of the individual activities, then it is known as potentiation.
Although, in the case of mixed preparations, this effect is given prominence
by the manufacturers, one should not forget that it is not quite simple
to show the experimental proof of a potentiation, as it takes place very
rarely.
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(The writer is the Deputy Director of Drugs Control, West
Bengal)
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