The recent Bombay High Court’s direction to State’s Food and Drugs Administration to consider issuing a circular for doctors pointing out the side effects of the drug 'thalidomide', which is prescribed to pregnant women for nausea and morning sickness is matter of grave concern. The drug has been banned for use in pregnant women in 1960s after the infamous thalidomide disaster which affected more than 10 thousand babies across the world barring few countries. It is difficult to understand how its use continues and affecting people! In this reported case, the petitioner alleged that he suffers from disorder which affected two fingers of both of his hands as result of thalidomide which was prescribed to his mother. Though the case was regarding the disability of the person denying the medical admission, it raised the issue of lack of information at prescribers’ point to have rational prescribing at least to avoid prescribing banned drugs. Let’s look at the thalidomide history and how it has influenced the drug use scenario.
The drug was synthesized in 1956 by a German company, Chemie. The invention of thalidomide was the result of a new venture for the company which used to make cosmetics and household products. The company had little or no experience on pharmaceuticals. Thalidomide showed considerable promise (exhibited considerable promising result/showed considerable effect) as a sleeping tablet and as an alternative to barbiturate. It had better safety profile than barbiturate as overdosing 100 times the normal dose was not lethal. On the contrary, few tablets of barbiturate were enough to kill. This was the time when barbiturate overdoses were outnumbering all hospital admissions of attempted suicides. Dogs were reported to have survived consuming amount of thalidomide that were one thousand times the dose required to make them sleep. The patients who attempted suicide with thalidomide had survived after consuming doses of at least one hundred times the normal dose. Besides, unlike barbiturates it did not have the risk of ‘hangover’ effects that might affect driving or operating heavy machineries.
The company started marketing thalidomide in Germany in October 1957 under the name of Contergan. Its equivalent Distaval was marketed in England. It was hailed as “tranquiliser of the future”. Within a year of thalidomide’s introduction in Germany, an extremely rare birth deformity began to appear. Babies were born with short, fin like flaps instead of normal arms and legs. It was in November 1961, a German paediatrician declared that the outbreak of this gross malformation, phocomelia, was due to the use in the pregnancy of the new hypnotic drug. In 1961 December, the first report of association was published in a widely circulated medical journal indicating that thalidomide might be human teratogen. The number of cases of phocomelia had mysteriously increased from 12 in 1959, to 83 in 1960, to 360 in 1961 in Germany alone. It was estimated that more than 10,000 babies of twenty countries were the victim of thalidomide. Of these, around 50 per cent (5000) survived and 1600 of whom eventually needed artificial limbs. The drug was finally withdrawn in 1961.
In 1960, a US pharmaceutical company, Merrell Pharmaceuticals, applied for permission to market thalidomide in USA. By this time many countries had permitted its use. In October 1961, the newly joined medical officer, Dr. (Ms) Frances Kelsey, was assigned the task of supervising the approval process of thalidomide. At that time, US FDA had to reject the approval within 60 days or automatically allow marketing. Though the company was eagerly waiting for its approval, Kelsey kept on stalling after each 60 days period rejecting the application incomplete. She was apprehensive of some data: one of the side effects was mild neuritis or tingling of nerves. She was trying to correlate her research of fifteen years before that the neuritis of this type in pregnant animals resulted in deformed offspring. She was just waiting for little longer before making a decision which paid. Then of course, the non-lethal but shocking adverse effect of thalidomide was known to the world. While the children of more than 20 countries including UK, Australia, Belgium, Switzerland, were affected by this thalidomide, FDA medical officer, Kelsey saved the America by her heroic ‘no’ to thalidomide despite pressure. In 1962, Dr. Frances Kelsey was awarded the President’s Gold Medal for distinguished service.
A review of the experimental work carried out with thalidomide before marketing revealed that inappropriate toxicological data had been published and animal findings were misinterpreted. Thalidomide disaster had taught many lessons and is also a classic example to cite:
• A clear understanding of benefit and risk: No medicine is absolutely safe. It is the benefit:risk ratio that makes the usefulness of substance as medicine. Thalidomide has now made a comeback as drug for refractory multiple myeloma and leprosy. In these patients, it outweighs risk in favour of benefit, provided it is not given to fertile women.
• It is not that everyone is at the same risk of a particular adverse effect. Women who do not have child bearing capacity have no risk at all.
In spite of so much negative publicity of thalidomide, this appears to be still used for nausea and alleviating morning sickness. Currently, it is indicated along with dexamethasone to treat multiple myeloma; alone or with other medications to treat and prevent skin symptoms of erythema nodosum leprosum (ENL in leprosy). It treats multiple myeloma by strengthening the immune system to fight cancer cells. It also treats ENL by blocking the action of certain natural substances that cause swelling. It is also useful treating certain complications of human immunodeficiency virus (HIV) such as aphthous stomatitis, HIV-associated diarrhoea, HIV-associated wasting syndrome, certain infections, and Kaposi's sarcoma and several other conditions. But its use is severely restricted. It is not suitable for pregnant women or the women who is likely pregnant. The man taking thalidomide is advised to wear condom or avoid sex as thalidomide is present in semen. The above information must be made available to the doctors and to patient as well to promote appropriate use of thalidomide. This would also prevent reoccurring of another thalidomide disaster, perhaps one of the greatest human tragedies. Our drug regulatory authorities should awake to ensure the safe and effective use of the medicines.
(The authors are with Department of Pharmacy, Annamalai University, Annamalai Nagar, Tamil Nadu 608 002)