Need For Withdrawing Drug From The Market
Unexpected adverse effects, or SUSARs (untoward and unintended response to a study drug, which is not listed is the applicable product information) harmful interactions, continued irrational use and not adequate risk management plan for the marketed product.1 The adverse effects are detected though a process of regular monitoring after the drug is released called pharmacovigilance, which is now dominant process in country regulated through Pharmacovigilance Programme in India, which is steered by Central Drugs Standard Control Organization, New Delhi. Fixed dose combinations are nearly 4 times more in India, than the developed countries, the basic reason for their introduction into market was better drug compliance, rather taking the two drugs separately. In the domestic market, FDCs (Fixed drug combinations) were contributing to > 50 % sales in the market. The rationality of FDC is not known much to clinicians. The Drugs Technical Advisory Board recommended that "there is no therapeutic justification" for the ingredients contained in the 344 FDC drugs and that these medicines "may involve risk to human beings".2 and thus these were removed from Indian market in March 15th 2016.3
Spectrum of withdrawal
The drugs withdrawn globally in the past decade were nonsteroidal antiinflammatory drugs (28%), antidiabetics (14.28%), antiobesity (14.28%), antihistamines (14.28%), prokinetic drugs (7.14%), breast cancer and infertility drugs (7.14%), irritable bowel syndrome and constipation drugs (7.14%) and antibiotics (7.14%).4 The widely used anti-obesity drugs fenfluramine and dexfenfluramine have been recalled in the various countries in the wake of continuing reports that their use is contributing to heart-valve defects. Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions.
Drugs may be withdrawn even after they are available in the market for a decade or longer. Examples of such drugs include are Rosiglitazone, Rofecoxib, Gatifloxacin, and Rimonabent formulations used in the market over a decade.
Table 1
Chronology of drug withdrawal of some vital molecules
It has been shown that the higher the fluoroquinolone dose ( Sparfloxacin , Grepafloxacin , Moxifloxacin) and serum AUCs, the higher the QT prolongation risk. Moxifloxacin is used to evaluate the drugs which can cause relative QTc prolongation.
There is a paradox, there are certain drugs not available in US and EU but are still marketed in India such as Analgin , Droperidol, Furazolidone, Nitrofurazone, Oxyphenbutazone , Nimesulide and Piperazine. However, the Union Ministry of Health and Family Welfare finally had decided to suspend the pediatric use of the Nimesulide suspension from 10 March 2011 Nimesulide formulations are not indicated for use in children below 12 years of age. The drug was banned in 2000 in various countries like Switzerland, Spain, and United states.5
In 2011, Pioglitazone was withdrawn from the French market owing to a potential risk of bladder cancer. U.S. Food and Drug Administration (FDA) is informing the public that use of the diabetes medication Actos (pioglitazone) for more than one year may be associated with an increased risk of bladder cancer.6 Information about this risk will be added to the Warnings and Precautions section of the label for pioglitazone-containing medicines. In India drug was withdrawn from Indian market but was reintroduced in Indian market as safety concern was only in animal studies and there were cost constraints
As evident from pie, most of drugs have been withdrawn due to Hepatoxicity, Cardiotoxicity, Neurotoxicity and the abnormal Haematological profile.
Recently, FDA has found N-nitrosodimethylamine (NDMA) levels in some ranitidine products increase with time and temperature posing a risk to consumers, and therefore the agency has requested the withdrawal of all ranitidine products from the U.S. market. In September 2019, Ranatidine was withdrawn by many generic companies in India and then it was reintroduced. Sartans such as Candesartan and Olmesartan also have such impurities.
Cerivastatin was approved in 1997 in US. Low doses were effective (0.2mg, 0.3mg and 0,4mg) It is indicated as an adjunct to diet to reduce elevated Total-C, LDL- C, apo B, and TG and to increase HDL-C levels in patients with primary hypercholesterolemia and mixed dyslipidemia High dose cerivastatin {0.8mg) along with Gemfibrozil 600mg caused Rhabdomyolysis in patients. This drug—drug interaction was implicated fatalities in the United States and Spain Cerivastatin was withdrawn on 9th August 2001.7 Cerivastatin was withdrawn from the market because of 52 deaths attributed to drug-related rhabdomyolysis that lead to kidney failure. FDA restricted Rosiglitazone use in February 2010 after studies linked the drug to increased risk of heart attacks. Rosiglitazone was also withdrawn from the New Zealand market in April 2011.
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