Millions of unapproved formulations and products of fixed dose combinations (FDCs) available in India in three therapeutic areas — analgesia, anxiety/depression and psychosis — are unsafe and at times dangerous or even lethal, as in the case of anti-psychotic. In contrast, 98 per cent of metformin FDCs to treat diabetes has been approved by the Central Drugs Standard Control Organisation (CDSCO).
Approval by CDSCO has been made mandatory for FDCs since 1961. Several amendments to the rules, particularly the last one in 2002, have only made it explicitly clear. Yet, the proportion of unapproved FDC formulations did “not decrease overall” after May 2002.
A fixed dose combination is one that contains two or more drugs combined in a fixed ratio of doses and available in a single dosage form.
“Multiple formulations [in the four therapeutic areas studied], most without CDSCO approval [for efficacy and safety], included drugs banned, restricted, or never approved internationally owing to adverse effects,” notes a paperpublished last week in the journal PLOS Medicine . Over 12 per cent of nonsteroidal anti-inflammatory drugs (NSAID) FDCs sales volume contain drugs that have either been “withdrawn” from the market or have had their “use restricted.”
Also, many NSAID FDCs available in India contain muscle relaxants and enzymes that have been approved as a single dosage form in the U.S. and UK but never as a fixed dose combination.
“Most of the FDC formulations available in India [in the four therapeutic areas studied] were unavailable in either UK or the U.S.” the authors note.
The study by Patricia McGettigan from the London School of Medicine and Dentistry, London and others also found that even in the case of approved formulations and products, “numerous” FDCs were marketed “before the CDSCO approval date.” Worse, since 2001, the CDSCO has approved some new drugs even “without clinical data” for efficacy and safety. And the grounds on which approval has been granted are not published.
With pharmacovigilance being at a nascent stage and reporting of adverse events being low, the absence of information on adverse effects of even approved FDCs, therefore, does not mean they are safe.
“Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally,” the authors recommend.
This is the first time an empiric study of FDCs available in India has been undertaken.
The researchers found that over 73 per cent of the 124 NSAIDs (analgesia) FDC formulations marketed in India were unapproved. The unapproved FDC formulations to treat depression/anxiety were 81 per cent and 70 per cent in the case of anti-psychotics. Contrastingly, only 20 per cent of the 25 metformin formulations for diabetes sold were unapproved.
The multiple unapproved FDC formulations have, in turn, given rise to hundreds of unapproved FDC branded products. Forty-three per cent of 2,739 NSAIDs products, 76 per cent of 301 antidepressanats/benzodiazepines products and 78 per cent of 211 anti-psychotics products and only 2 per cent of 536 metformin products available in the market were unapproved by CDSCO.
What makes some fixed dose combinations unsafe and even dangerous is when multiple drugs from the same therapeutic group are combined or when centrally acting drugs are clubbed together. If the former compounds the risk of adverse effects, the latter makes it difficult to undertake separate dose adjustments of the drugs that are combined.
The huge availability of unapproved FDC formulations was reflected in the proportion of sales volume and sales value in 2011-2012. Though the sales volume of unapproved NSAID formulations was only 28 per cent, the sale value was as high as 61 per cent. In the case of unapproved antidepressanats/benzodiazepines formulations, the sales volume of 69 per cent led to a sales value of 57 per cent. It was 43 per cent sales volume and 6 per cent sales value in the case of anti-psychotic formulations.
Despite the sale volume of unapproved metformin formulations being a meagre 4 per cent, the sales value was at an alarming 99.7 per cent.