In 2016, the Union Health Ministry prohibited the sale of 344 fixed-dose combination (FDC) drugs. However, after drug manufacturers challenged the order in the Delhi High Court, only 14 drugs came to be banned.
The government said, “there is no therapeutic justification for these FDCs and they may pose a risk to human beings,” and that the action was taken in “the larger public interest”. However, countless irrational FDC drugs continue to plague the market, despite it being well-known that they are unscientific and harmful to patients.
Combos gone wrong
The Central Drugs Standard Control Organization (CDSCO) defines FDC drugs as “products containing two or more active ingredients used for a particular indication(s).” The discovery of FDC drugs — once considered to be a step towards better disease control — has now become a huge threat for India’s public health system.
When used rationally, the combination of drugs in FDCs can enhance each other’s actions and reduce the dose required compared to when they are taken individually. For example, a combination of metformin and glyburide has been reported to control diabetes at lower doses when given as an FDC compared to when given as separate tablets.
FDCs also promote drug compliance by reducing the number of pills needed for people on multiple medications. For example, earlier, four different tablets were prescribed to treat tuberculosis, but now an FDC of the four tablets is prescribed for treatment.
A 2015 study published in PLOS Medicine reported that, in India, there were 2,739 FDCs for non-steroidal, anti-inflammatory drugs (NSAIDs) — commonly used painkillers. While 28 per cent of these FDCs were unapproved in India, 12 per cent had been banned internationally. Similarly, 69 per cent of the FDC drugs used as antidepressants and antipsychotics in India were unapproved.
An analysis of a thousand random prescriptions in the Jhalawar district of Rajasthan showed that 86.7 per cent of the FDCs prescribed by doctors were unnecessary, with the most common irrational FDCs being antibiotics, anti-inflammatory drugs and anti-hypertensive drugs. They are contributing to antimicrobial resistance and are also associated with severe life-threatening side effects.
The poor functioning of drug regulatory body, CDCSO, has led to harmful FDCs being sold in the market. For example, an ointment widely sold over-the-counter for skin rashes contains ketoconazole (antifungal), neomycin (antibiotic), iodochlorhydroxyquinoline (a combination of antifungal and antiprotozoal), and clobetasol propionate (a potent steroid). A combination such as this not only harm patients but also adds to unnecessary medical expenditure.
Another irrational FDC contains a combination of Telmisartan and Ramipril. These two drugs lower blood pressure by lowering Angiostensin-II — a chemical that constricts blood vessels and raises blood pressure. Manufacturers lower the level of the chemical through different mechanisms and their combination has been shown to cause side effects such as hypotension and kidney injury.
Why do irrational FDCs exist?
There is a historical reason — to escape the price regulatory net. In the past, there was strict regulation of the prices of “essential” drugs. The government would fix the price based on the cost of materials, conversion cost and a small profit. One way to escape this was to add ingredients so that the final product was not on the list of drugs for which the price was controlled.
For example, if the price of a diclofenac cream used for pain relief was regulated, adding an ingredient that was not price-controlled, such as menthol and methyl salicylate, would allow the manufacturer to argue that it was not just diclofenac and therefore outside the purview of price control. Alternatively, adding a “herbal” ingredient like capsaicin also enabled the manufacturer to claim that it is a proprietary formulation, exempt from price control.
This loophole was closed with the Drug Price Control Order, 2013, where price of a drug would be controlled if any of its ingredients is listed for price regulation.
But, a vast majority of drugs are still not covered by price-control regulations. When all generic brands have the same active ingredient, it is impossible to show that one brand is better than the other. One great marketing idea was adding ingredients to make the product look like it was “better value” than the competition. For example, having an antibiotic, antifungal, antiprotozoal, a steroid and pain relief in the same ointment might sound better than an ointment with just an antibacterial.
FDCs prey on the ‘value for money’ attitude of the Indian patient by offering a ‘buy one, get one free’ model. When competition caught on to this gimmick, it became a race for ‘buy one, get many free’!
The way forward
The dangers of irrational FDCs have been well documented for decades. The 2013 guidelines for FDC approval by the CDSCO states: “FDCs must be based on convincing therapeutic rationalisation and be carefully justified and clinically relevant.” This applies to manufacturing, import and marketing approval of every FDC in the country. The extensive guidelines mandate the combination of drugs and their respective doses be scientifically justified. The presence of countless irrational FDCs in the market highlights the urgent need for these guidelines to be strictly implemented.
Lastly, doctors need to stop prescribing these unnecessary FDCs. While proper implementation of the existing regulations is the ultimate solution, it is also the responsibility of healthcare providers to safeguard the public health by educating them about irrational FDCs and prescribing only rational FDCs when needed.
(Dr Sharma is a public health physician and founder of Nivarana, a public health advocacy and information platform. Neelakantan is Principal Lawyer at Amicus)