The health of 120 million patients in India is in jeopardy because of the proliferation in the past decade of unapproved and unregulated combination drugs commonly used as anti-inflammatory, antidepressant and anti-psychotic medication, a new study has found.
The research findings are especially troubling for people who are depressed because 8-in-10 antidepressant and 7-in-10 anti-psychotic combination drugs in India don’t have the proper approval. Worldwide, depression has already taken over as the leading cause of disability but its treatment in India is largely unregulated.
Combination drugs – also known as fixed-drug combinations – is the term used for two or more drugs that are taken together in a single ‘dosage form’ like a tablet or capsule. They comprise a mix of chemical compounds that act on different enzymes in the body. Combination drugs are usually used to tackle prevalent infectious diseases like malaria, tuberculosis and HIV/AIDS. In India alone, from 2002 to 2013, 732 million units of combination drugs were sold, worth Rs. 1,820 crore.
The government body responsible for regulating the licensing, manufacture and distribution of combination drugs is the Central Drugs Standard Control Organisation. This is a body whose diligence has often been questioned, notably by the Rajya Sabha in 2012, when it was pulled up for not having a permanent committee of medical experts attached to it.
Now, for the first time, a team of researchers from Mumbai and London has estimated the scale of unregulated combination drugs circulating in the market. Using data from the CDSCO and PharmaTrac, a database of national drug sales, the team estimated that 76 formulations of combination drugs were available in the market that weren’t approved by the CDSCO. Their total value: Rs. 470 crore.
Overall, since 1961, the CDSCO has approved only 69.3% of all combination drugs available in India.
The researchers, affiliated with the Foundation for Research in Community Health (Mumbai), the London School of Medicine and Dentistry, and the Queen Mary University of London, published their findings in the journal PLOS Medicine on May 12.
The 76 unapproved formulations together made up 129.3 million combinations that had been sold. They were split into four categories: non-steroidal anti-inflammatory (NSAID), metformin, antidepressant and anti-psychotic drugs.
While there are rigorous regulations for combination drugs used to treat tuberculosis and HIV/AIDS, and for contraception, the researchers found 73% of NSAIDs and 81% of antidepressant combination drugs don’t have CDSCO approval. They also found that 20% of metformin and 70% of antipsychotics are unapproved.
In 2007, the CDSCO had banned the sale of 294 combination drugs. However, the drugs’ manufacturers were able to obtain a stay from the Madras High Court on grounds that the state government had provided them with the licenses to manufacture and sell the combination drugs. The conflict between the CDSCO and state authorities exists thanks to some ambiguously framed rules in the Drugs and Cosmetics Rules 1945, which empowered state-level licensing bodies to make decisions overriding CDSCO approval. Though the rules were amended in May 2002, the CDSCO has taken few active measures to ensure manufacturers operating with old licenses had to get new ones – resulting in cases like the one still pending in the Madras High Court.
In the meantime, the lack of regulatory oversight means not only low-quality but also potentially dangerous combinations of drugs. What’s worse is that certain combination drugs may not be as effective as they promise to be.
In a 2008 article in the Journal of Clinical Pharmacology, CS Gautam and Lekha Saha of the Government Medical College and Hospital, Chandigarh, highlight the case of ‘irrational combinations’, where two drugs act on the same enzyme inside the body and therefore can’t provide better treatment than if just one of the two drugs were involved.
They use the example 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”.
Irrationality has been the ground for nimesulide, and dextropropoxyphene, having been withdrawn in multiple countries. When consumed as part of NSAID combination drugs, nimesulide causes liver toxicity while dextropropoxyphene can be fatal. In India, however, 723 million tablets/capsules of nimesulide and 21 million tablets/capsules of dextropropoxyphene combination drugs were sold in 2011 alone.
As it turns out, the painkiller morphine – renowned for its use in end-of-life palliative care – is either not readily available in parts of India or, when it is, is not readily prescribed by doctors wary of its effects. The result is that dextropropoxyphene is often the only available painkiller in rural areas. However, thanks to its involvement in dangerous combination drugs, the Ministry of Health and Family Welfare suspended its manufacture, distribution and sale in May 2013.
Note: This article was updated on May 17, 2015, to include the fact that the manufacture, distribution and sale of dextropropoxyphene was suspended by the Ministry of Health and Family Welfare in May 2013, and that the drug was often a substitute for morphine.