Drugs banned in other countries, still prevailing in India, a vital matter of concern—A narrative review

Abstract

Drugs and their formulations are mainly used in the prevention and treatment of disease or disorders; out of such drugs, only some are considered to be essential and life-saving, whereas others remain substitutes for each other. When some serious adverse effect is faced by a general population on the consumption of the particular drug, the adverse side effects are monitored through pharmacovigilance; when the hazard overshadows the benefit, then the drug is proposed for a ban in the country. Some drugs potentiate the adverse effect only when it is in combination with another drug, which is considered to be irrational; in such situations, the Fixed Dose Combinations FDC is banned but not the single drug. Banned drugs are still available in India, and this might be due to the lack of awareness and knowledge among clinicians and the persistence of loopholes in Indian laws governing the approval and manufacture of drugs. The government needs to enforce laws and increase drug information centers and ensure their proper functioning, from where the update on each drug will be provided to doctors and the general population.

INTRODUCTION

The prevalence of diseases is constantly increasing in the present-day scenario, and the major concern of drug manufacturers, doctors, and other healthcare professionals is to guarantee the quality of drugs with determined therapeutic advantages and low adverse side effects.[^1,2,3] Unanticipated adverse side effects, superfluous toxic effects, accessibility for safer substitutes, detrimental interactions, irrational combinations, and the risk of management failures are the key factors that decide whether to use or ban a drug. When drugs are found to be unsafe in post-marketing surveillance conducted, then developed countries immediately impose a ban through regulatory bodies on the manufacture and sale of a drug.[⁴] However, in India, imposing a ban on a drug is a lengthy and time-consuming procedure which is the key reason for the persistence of banned drugs in the market even though the drug is banned in other countries.[^2,4] Another major reason for the availability of banned drugs is that adequate ADR information about these drugs has not been conveyed.[⁵] The present review elaborately discusses the drugs banned in other countries still available in Indian markets and the reason for their persistence and compares the drug safety monitoring systems in developed countries and affords allegations for improving a system in India that can warrant the safety and efficacy of drugs.

PHARMACOVIGILANCE

Centers for pharmacovigilance have been set up in most countries. Among those, Uppsala Monitoring Centre in Sweden is the international collaboration center. In India, the National Pharmacovigilance Program (NPP) was set up by the Ministry of Health and Family Welfare in AIIMS, New Delhi, in the year 2010 to collect adverse drug reaction (ADR) information throughout the country. The NPP encompasses a national coordinating center that obtains ADR information from individual pharmacovigilance centers located all over the country about the cause, issue, and the employees involved in an adverse drug event via a VIGIFLOW software interface functioned by Uppsala Monitoring Centre. The data generated by pharmacovigilance are beneficial in educating healthcare professionals about ADRs and as the official guideline for drug use. It has a significant part in the rational use of medicines as it offers the basis for assessing the safety and efficacy of drugs.[⁶]

The events involved in pharmacovigilance are

1. Post-marketing surveillance and other methods of ADR monitoring such as intentional reporting by doctors, prescription event monitoring, electronic medical record connection, and other cohort/case-control studies. Voluntary reporting depends on the ingenuity and preparedness of health professionals. It is negligible in India, whereas even in developed countries, less than 10% of ADRs are reported voluntarily. Generally, instantly occurring reactions and those that are melodramatic are reported. Even though rare reactions can be perceived by this method, it does not provide the incidence of the reaction.
2. Broadcasting of ADR facts through “drug alerts,” “medical letters,” advisories sent to healthcare professionals by pharmaceuticals, and regulatory agencies [such as the Food and Drug Administration (FDA) in the USA, MPA in Sweden, NAM in Finland, etc.].
3. Changes in the cataloging of drugs indicate constraints in use or statuary warnings, precautions, or even taking away the drug.[^6,8]

ADVERSE DRUG REACTIONS

Mostly all drugs are capable of inducing an adverse side effect and whenever a particular drug is been prescribed a risk is reserved. The magnitude of risk has to be taken into consideration along with the magnitude of expected therapeutic benefit in determining whether to continue or terminate a particular drug in a given patient. For example, even a risk of immunosuppression with immunosuppressive agents and steroids may be justified in the case of organ transplantation, whereas mild drowsiness caused by antihistamines in treating the common cold and allergies may be unacceptable. ADRs have been classified as augmented (type A) and bizarre (type B).[^9,10]

ADR REPORTING

Intended reporting of ADRs by healthcare professionals is considered to be a foundation in the management of ADRs. Reporting is generally commenced electronically through an online portal and verbally by mailing to the concerned organization. The use of electronic reporting is gaining popularity in the present-day scenario Table 1.

Table 1: ADR Reporting Organization in Various Countries

REGULATORY STATUS OF DRUGS IN INDIA

Over the past decade, an immense market for irrational FDCs comprising banned drugs in combination has been broadening up in India; this has been ascribed to the profile-raising actions of the pharmaceutical companies tormented unswervingly toward the consumers or clinical practitioners. 122E of the Drug and Cosmetics Rule recommends that an amalgamation of two or more medications is considered to be a “new drug,” and all novel combinations have to be legitimately legalized by the Drugs Controller General, India (DCGI); this is made considerate because by amalgamating two or more drugs, the safety, effectiveness, and bioavailability of the distinct active pharmaceutical ingredient might fluctuate. In the present-day scenario, the practice of approval is as follows: State drug controllers (SDCs) can/do offer certificates for approval and marketing of new combinations, although they do not possess this legal authority. Once permission for a drug is permitted by a SDC, it can be traded/sold in any state of the country, although it is neither approved by the DCGI nor by other SDCs. The Indian laws governing the marketing and accreditation of drugs are not appropriately defined. The pharmaceutical companies take advantage of these ambiguities and endure to market irrational drugs and in turn get benefited from high earnings.[^3,4]

The Drug Technical Advisory Board (DTAB) is the final authority in imposing a ban on the drug, and steps in processing a ban involve assigning an executing committee that examines the harmful effects of the drug, and then the results are reported to the DTAB, which makes the government then issue a banning order; following this, the DCGI notifies the issue on the ban to SDCs, and then the SDCs allocate authorities and are instructed to carry out inspections. Recently, the Ministry of Health and Family Welfare has banned around 336 fixed drug combinations vide gazette notification dated 10/3/2016.[^3,4,5]

GLOBALLY DISCARDED DRUGS PREVAILING IN INDIA AND THE REASON FOR THEIR BAN

• *Metamizole preferred for its analgesic action has been banned globally due to the risk of bone marrow depression and agranulocytosis.
• *Nimesulide has been banned for pediatric use [below 12 years of age] in India on February 12, 2011, by the Union Ministry of Health and Family Welfare. This drug has been withdrawn due to fulminant hepatic failure in the year 2000 in various countries but is still being prescribed by some elder practitioners in India due to its par excellence in counteracting inflammatory pain.
• Prophiphenazone indicated for inflammatory pain has been discarded due to the adverse effect of bone marrow depression.
• Nefopam, the most preferred analgesic for post-operative pain, has been banned due to the higher incidence of occurrence of epilepsy.
• *Oxyphenbutazone: This NSAID has been banned as it causes bone marrow depression.
• Some of the *paracetamol formulations have been banned in a few countries due to analgesic abuse nephropathy. As such, combining paracetamol with other NSAIDs/other analgesics is considered to be irrational and such combinations are banned in a few countries, whereas in India, these formulations are still available.
• Nitrofurazone, available as an antibiotic cream, has been withdrawn due to its carcinogenic property.
• *Phenylpropranolamine, prescribed for cold and cough, has been withdrawn due to its adverse effects such as dizziness and stroke.
• Droperidol used as an anti-psychotic has been banned as it causes irregular pumping of the heart.
• Cerivastatin, a hypercholesterolemia drug, has been withdrawn on account of rhabdomyolysis.
• Phenolphthalein, a laxative, has been discarded due to its carcinogenicity.
• Cisapride has been withdrawn due to the occurrence of irregular heartbeats.
• Fenfluramine, an antiobesity drug, has adverse cardiotoxic effects.
• Practolol (banned in India too but still prescribed) has been banned due to adverse side effects like occulo-mucocutaneous syndrome and damage to lacrimal glands.[^3,4,6,11,12]

There are some drugs [*mentioned in the above paragraph] been constantly prescribed by clinicians and have been rapidly sold in the Indian market. Analgin (metamizole) is manufactured and marketed due to its excellent pain-relieving properties, but consumers are not aware of its adverse effects; a ban on nimesulide has been proposed in India, but some old practitioners keep prescribing this drug, which might be due to their lack of awareness regarding an update on the drug. Phenyl propanolamine (commercial examples: Vicks action 500) has been banned an infinite number of times in the Indian market but also it is still prevalent due to commercial advertisements by Kollywood and Bollywood stars. Also, over-the-counter analgesic paracetamol formulations have been banned in countries such as Syria, Saudi, Bangladesh, Iran, and Kuwait because of analgesic abuse nephropathy, but it is followed in India due to its par excellence as an antipyretic drug Table 2.

Table 2: Individual Drugs Withdrawn from India to Date[^{3 , 4 , 6 , 7 , 11 , 12}]

Why globally discarded drugs still prevail in India

• Inadequate monitoring by regulatory authorities
• Unawareness among healthcare professionals and patients
• Lack of coordination/communication between the DCGI and SDC
• Commercial advertisements by pharmaceutical companies to promote the drug
• Self-medications
• Underreporting of ADRs
• Poverty
• Non-availability of appropriate drugs at right time and their high cost[³]

BLACK BOX WARNINGS: The FDA issued black box warnings to vigilant healthcare professionals about serious ADRs. (Black box is a terminology) “Black box” is a term that states to the datum that at the starting point of the package insert of the drug there is factually a black box encircling the written warning to attract the attention of the purchaser. The FDA newly made a strenuous effort to embrace more black box warnings on more products to upsurge public safety[¹³] Table 3.

Table 3: Few Examples of Black-Box Warnings[^{13 , 14}]

Suggestions regarding improvement of drug safety in India

A few commendations to augment drug safety in India comprise the following:

• Prescribing a medication for which ADR information is available.
• Providing adequate information to patients when new drugs have been prescribed, sensitizing them regarding probable ADRs, and approval of novel drugs with attention to diseases for which safe substitutes are already present.
• Exhibiting banned drugs in pamphlets and newsletters in every pharmacy will play a major role in creating awareness among the general population.
• Indication of the drug approval date and black box cautions [FDA issued a black box warning to vigilant healthcare professionals about serious ADRs] on the label of medications for creating awareness among physicians and pharmacists in prescription or dispersal of banned drugs.
• Advertisements through mass media about banned drugs and exhibiting them in public transport sectors might be useful in creating awareness among the general population.
• Creating awareness by the NPP regarding banned drugs and establishing a committee by the DTAB to regulate banned drugs with severe ADRs; also, the NPP should work on creating a positive attitude among healthcare professionals so that reporting about ADRs becomes an acknowledged and continuous practice.
• Creating awareness about ADR reporting and introducing reporting methods for patients will enormously intensify the reporting of cases. A concurrent verification process can be implemented to authorize that the ADR reported by the patients is potentially associated with the use of a particular drug.[¹⁴]

CONCLUSION

Creating awareness among clinicians and healthcare professionals regarding the serious adverse reaction of banned medications, notifying and educating the general population about internationally banned drugs, and the risk associated with their use so as to retain them in stride with the aware residents of developed countries: These can be accomplished by the inauguration of drug information centers to make available the rationalized, critically appraised, and unbiased data pertaining to the drugs for healthcare professionals and consumers.[³] Educating medical graduates at the undergraduate level regarding the banned drugs so as to hold back the prescription of such drugs in upcoming practice. Evaluating the safety and effectiveness of any novel drug beforehand and familiarizing it in the market by the Drug Controller General of India.[^4,5] Strict implementation of laws by a regulatory body (DTAB and DCGI) to take speedy ingenuity to discard drugs when found hazardous to consumers, even nowadays banning procedure is long-lasting in India, which produces manufacturers an ample stretch to manufacture the drug in more numbers. DTAB, the final authority in India for banning drugs, is about to strictly withdraw the licenses of the pharmacists who stock banned drugs in bulk. This condition dictates the nomination of more drug inspectors to execute appropriate and consistent inspections of drug dispensing centers.[^15,16] A pharmacovigilance system can be made effective by establishing the engrossment of each category of healthcare professionals and constructing ADR reporting as mandatory like in developed countries. To forever stop the practice of prescribing banned drugs in our country, a collective effort by clinical practitioners, pharmacists, researcher scholars, and drug manufacturers accompanied by the implementation of strict laws by regulatory authorities is needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.