Transcript

Overnight ban on Fixed Dose Combination Drugs by Government of India: Impacts & Analysis on Indian Pharmaceutical Industry

Dissertation Report

March-April, 2016

Submitted By:

Akshay Saxena

MBA (Pharmaceutical Management)

Faculty of Management & Information Technology

Jamia Hamdard

Session: 2014-2016

Submitted to:

College Mentor:

Dr. Shibu John

Head of Department

Jamia Hamdard

Declaration

I, Akshay Saxena hereby declare that the project entitled “Overnight ban on Fixed Dose Combination Drugs by Government of India: Impacts & Analysis on Indian Pharmaceutical Industry” is my original and exclusively my own work. I further declare that the work is my own authentic piece of work and has not been submitted at my organization/institute/university for personal/academics gains and benefits or award of any degree/diploma/certificate.

Akshay Saxena

MBA (Pharma Management)

Enrolment No.: 2014-542-001

Jamia Hamdard

New Delhi

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Acknowledgement

I wish to express my gratitude to the almighty God for giving me the strength to perform my responsibilities as an intern and complete the report within the stipulated time.

I was given the opportunity to prepare a report for my dissertation work under supervision of our honourable supervisor of internship. It was great opportunity for me to augment my knowledge about analysing critical data and information. This report would have been incomplete without the help of certain people. The purpose this part of the report is to pay a tribute to all of those cooperative people who gave their precious time to help me and without whose assistance it would have been impossible to finish the report.

I would also like to thank and express my gratitude to Dr. Shibu John, Head of Department, Jamia Hamdard for his invaluable feedback and support.

I am also grateful to my parents, Harsh Shah and my other friends without their valuable input, this report and research could not have been successful.

In the end, it is necessary to mention that this report is the result of days of hard work. I am thankful to the people who have contributed greatly behind the completion of the report. Without their help, this report would have not been even completed within the deadline.

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Executive Summary

On 10 March 2016, the Union Health Ministry banned 344 fixed drug combinations by issuing a gazette notification. Fixed dose combination (FDC) drugs including painkillers, anti-diabetic, respiratory and gastro-intestinal medicines will have an impact of 3.1 per cent or Rs. 3,049 crore of the country's pharma retail market currently valued at 98,042 crores, according to a market based study.

The list is inclusive of a number of commonly used cough syrup solutions, as well as antibiotic combinations and analgesics. Majority of the combinations banned are sold over the counter. The government had recently constituted an expert committee in order to gauge how effective were the various drug combinations found in India. It was on the basis of the recommendations made by the said committee that the ban was imposed. However, it is expected that the industry will not take this lying down; in fact, some of the companies affected by the ruling may even seek judicial redress.

A lot of these medicines, thus developed, happen to have antibiotics in their make. They are also sold in an over-the-counter manner, thus, making it hard for authorities to carry out drug resistance measures properly. Recently, the Health Ministry had started a programme to reduce the casual and irresponsible manner in which antibiotics are consumed in India. As a result of that initiative, the government has now come up with a special schedule that requires chemists to check prescriptions before they sell medicines and also have records of the same. If they don’t observe these measures, they may face actions initiated by the government against them.

Even as the Union health ministry's ban on 344 fixed dose combination (FDC) drugs including painkillers, anti-diabetic, respiratory and gastro-intestinal medicines has made a sales impact of over Rs.10,000 crore, category of FDCs most impacted includes antibiotics, antihistaminic, caffeine and codeine combinations and NSAID.

Government has banned common household medicines Crocin Cold and Flu, D-Cold Total, Sumo, Oflox, Gastrogyl, Chericof, Nimulid, Kofnil, Dolo Cold, Decoff, O2, paediatric syrup T-98 and TedyKoff, as part of its decision to stop the manufacture and sale of FDCs.

Delhi High Court extends stay on ban of some drugs till 28 March

The Delhi High Court put on hold a ban that has been imposed on the sale and manufacture of more than 300 fixed dose combinations (FDC) medicines like D’Cold, Vicks Action 500 Extra and Benadryl. After resuming a hearing on pleas by 30+ pharmaceutical companies, the court decided to hold the ban till 28 March 2016. Previously, Delhi High Court had offered an interim relief on 14 March to Pfizer’s cough syrup ‘Corex’.

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Content

1.0 Introduction1.1 The Indian pharmaceutical industry 71.2 The Ban 91.3 List of banned FDC drugs 11

2.0 Literature Review 20

3.0 Justification/Rational 25

4.0 Objectives26

5.0 Research Methodology 274.1 Research Design4.2 Research Tools4.3 Data Collection

6.0 Study Findings

6.1 Reason for the ban of FDC drugs 296.2 Financial loss endured by the pharmaceutical companies 356.3 Measures taken by the pharma companies after the ban 426.4 Impact on consumers 44

7.0 Conclusion 45

8.0 Bibliography 50

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1.0 Introduction

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The Indian Pharmaceutical Industry

The Indian Pharmaceutical Industry has witnessed a robust growth over the past few years moving on from a turnover of approx. US $1 billion in 1990 to over US $30 billion in 2015 of which the export turnover is approximately US $ 15 billion. The country now ranks 3rd world wide by volume of production and 14th by value, thereby accounting for around 10% of world’s production by volume and 1.5% by value. Globally, it ranks 4th in terms of generic production and 17th in terms of export value of bulk actives and dosage forms. Indian exports are destined to more than 200 countries around the globe including highly regulated markets of US, West Europe, Japan and Australia. It has shown tremendous progress in terms of infrastructure development, technology base creation and a wide range of products. It has established its presence and determination to flourish in the changing environment. The industry now produces bulk drugs belonging to all major therapeutic groups requiring complicated manufacturing technologies. Formulations in various dosage forms are being produced in GMP (Good Manufacturing Practices) compliant facilities. Strong scientific and technical manpower and pioneering work done in process development have made this possible.

The Indian pharmaceutical industry currently tops the chart amongst India's science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. A highly organized sector, the Indian pharmaceuticals market is expected to expand at a CAGR of 23.9 percent to reach US$ 55 billion by 2020. It ranks very high amongst all the third world countries, in terms of technology, quality and the vast range of medicines that are manufactured. It ranges from simple headache pills to sophisticated antibiotics and complex cardiac compounds; almost every type of medicine is now made in the Indian pharmaceutical industry.

The Indian pharmaceutical industry is estimated to grow at 20 per cent compound annual growth rate (CAGR) over the next five years. India is now among the top five pharmaceutical emerging markets. There will be new drug launches, new drug filings, and Phase II clinic trials throughout the year. On back of increasing sales of generic medicines, continued growth in chronic therapies and a greater penetration in rural markets, the domestic pharma market to grow at 10-12 per cent in FY15 as compared to 9 per cent in FY14.

Recognizing the potential for growth, the Government of India took up the initiative of developing the Indian Pharmaceuticals sector by creating a separate Department in July 2008. The Department is entrusted with the responsibility of policy, planning, development and regulation of Pharmaceutical Industries. An assessment of the Indian Pharmaceutical Industry's strength reveals the following key features:

Strong export market- India exported drugs worth US$ 15 billion to more than 200 countries including highly regulated markets in the US, Europe, Japan and Australia. Large Indian pharma companies have emerged as among the most competitive in the evolving generic space in North America and have created an unmatched platform in this space. Indian companies are also making their presence felt in the emerging markets around the world, particularly with a strong portfolio in anti-infective and antiretroviral.

Large domestic pharma companies have continued to grow, assuming leadership position in many therapies and segments in the Indian market as well as creating a strong international exports back-bone.

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Competitive market with the emergence of a number of second tier Indian companies with new and innovative business modules.

Indian players have also developed expertise in significant biologics capabilities. Biologic portfolios while still nascent in India are being built with an eye on the

future. Multinational companies have continued to invest significantly in India and are

making their presence felt across most segments of the Indian pharma market. Companies have also begun to invest in increasing their presence in tier II cities and rural areas and making medical care more accessible to a large section of the Indian population.

Low cost of production. Low R&D costs. Innovative Scientific manpower. Excellent and world-class national laboratories specializing in process development

and development of cost effective technologies. Increasing balance of trade in Pharma sector. An efficient and cost effective source for procuring generic drugs, especially the drugs

going off patent in the next few years. An excellent centre for clinical trials in view of the diversity in population.

Indian pharmaceutical market segments by value

Anti-infective drugs command the largest share (16%) in the Indian pharma market.

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THE BAN

Since 1961, India’s drug controller has approved more than 1,200 combination drugs or FDCs (Fixed Dose Combinations), according to a list published on the website of the Health Ministry’s Central Drugs Standard Control Organization (CDSCO), the national drug regulatory body. But many have also been licensed on the state level without the approval of the central government.

It wasn’t until 1988 that the definition of a “new drug” under Indian law was amended to expressly include the combination of two or more already approved drugs.

What is a fixed-dose combination?

The term fixed-dose combination product is synonymous with fixed-ratio combination product. Both terms refer to a product that contains two or more active ingredients. Because the product is of a defined composition, the two (or more) ingredients are present in a fixed ratio. Hence the term “fixed dose” or “fixed ratio” combination.

Such a product may be available in more than one strength, each of which may itself be a fixed dose combination and may contain different ratios of active ingredients. For example, Augmentin Duo Forte® tablets contain 850 mg of amoxicillin and 125 mg of clavulanic acid (a ratio of 6.8:1) whereas Augmentin Forte® tablets contain 500 mg of amoxicillin and 125 mg of clavulanic acid (a ratio of 4:1). Different ratios can be rational in particular circumstances.

Advantages of fixed-dose combinations

The presumed advantages of FDCs include:

• Drugs that are normally given in combination are more conveniently prescribed and consumed as an FDC.

• Better patient compliance is claimed.• It is cheaper to purchase an FDC product than to purchase the products separately.• The logistics of procurement and distribution are simpler (which can be especially

important in remote areas).

Disadvantages of fixed-dose combinations

Critics of FDCs suggest that:

• FDCs discourage separate titration of each active ingredient. This is a particular problem when both of the active ingredients require dose titration. Indeed, it can be argued that the very existence of an FDC discourages adjustment of doses to the patient’s needs (if that is appropriate for the combination in question).

• When the active ingredients in question have different pharmacokinetics and/or pharmacodynamics, an FDC may not be appropriate.

• Unless both of the active ingredients are available as separate entities, FDCs encourage polypharmacy irrespective of whether it is appropriate for a particular patient.

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In 2007, the government tried and failed to get close to 300 state-licensed combination drugs withdrawn. In 2012, the government undertook another attempt to exert control over the FDC market. That followed a parliamentary report critical of the functioning of the CDSCO. The report also underlined the health risks posed by unapproved combinations.

For a long time in India, patients have been consuming drugs which are banned in various countries like the USA, Canada, Europe, Australia etc. The most common are like Nimesulide, Furazolidone, Phenylpropanolamine and other over the counter preparation are banned by USFDA due to their side effect on kidney, liver and nervous system. Unfortunately analgesic, antidiarrheal and cough preparations which are banned in other countries and are blindly used in India as over the counter drugs because of unawareness, lack of law enforcement and corruption.

All the formulations are meant for prevention or treatment of ailments and diseases, out of which only a few drugs are lifesaving and essential, rest of the drugs are substitutes of each other.

Banned drugs are drugs which are prohibited to intake as they artificially improve the performance but show various adverse effects more than therapeutic effects. Their production or use is prohibited or strictly controlled via prescription.

“Drug Controller general of India” is the highest authority in India to expand the approval of any drug or to ban a drug. Some of the dangerous drugs have been globally discarded but are available in India. The most common are like Nimesulide, Furazolidone and Phenylpropanolamine

On 10 March 2016, an expert committee, CDSCO (Central Drugs Standard Control Organization) found about over 300 of medicinal products to be irrational in nature which means that they could potentially harm patients who consumed them. Commentators pegged fixed dose combination or FDCs to constitute nearly 50% of the $15 billion domestic Indian pharma market. It is impossible to believe that such a large market exists without consumer demand to match.

Fixed-dose combination drugs are when a pharmaceutical combines two or more active drugs in a fixed ratio into a single dosage.

The full impact of the ban would be Rs. 3,800 crore a year on the Indian pharmaceutical industry.  The government had constituted a panel under Professor Chandrakant Kokate to review the fixed combination drugs. The panel, which had examined 5,518 drug combinations, had recommended in January 2015 that 963 drug combinations are irrational.

These medicines have been available for years – in some cases, over 30 years. To be sure, this doesn’t make it legitimate. If FDCs have been deemed to be unsafe for patients by experts, then we must accept the verdict. What is wrong is wrong and one should not defend it.

The move is aimed at curbing the misuse of such medicines in India, where nearly half the drugs sold in 2014 were so called “fixed dose combinations.”

Following is the list of FDCs that are now banned:

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S. No. Banned FDCs (Fixed Dose Combinations)

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1 Aceclofenac (SR) + Paracetamol2 Aceclofenac + Paracetamol + Famotidine3 Aceclofenac + Paracetamol + Rabeprazole4 Aceclofenac + Zinc Carnosine5 Acetaminophen + Guaifenesin + Dextromethorphan + Chlorpheniramine6 Acetaminophen + Loratadine + Ambroxol + Phenylephrine7 Acriflavine + Thymol + Cetrimide8 Acrivastine + Paracetamol + Caffeine + Phenylephrine9 Albuterol + Bromhexine + Theophylline10 Albuterol + Etofylline + Bromhexine + Menthol11 Alginic Acid + Sodium Bicarbonate + Dried Aluminium Hydroxide + Magnesium

Hydroxide12 Allantoin + Dimethieone + Urea + Propylene + Glycerin + Liquid Paraffin13 Ambroxol + Guaifenesin + Phenylephrine + Chlorpheniramine14 Ambroxol + Guaiphenesin + Ammonium Chloride + Phenylephrine +

Chlorpheniramine Maleate + Menthol15 Ambroxol + Salbutamol + Choline Theophyllinate + Menthol16 Ambroxol + Salbutamol + Theophylline17 Ambroxol + Terbutaline + Dextromethorphan18 Ammomium Chloride + Bromhexine + Dextromethorphan19 Ammonium Chloride + Dextromethorphan + Cetirizine + Menthol20 Ammonium Chloride + Sodium Citrate + Chlorpheniramine Maleate + Menthol21 Ammonium Citrate + Vitamin B 12 + Folic Acid + Zinc Sulphate22 Amoxicillin + Bromhexine23 Amoxicillin + Cefixime + Potassium Clavulanic Acid24 Amoxicillin + Dicloxacillin25 Amoxicillin 250 mg + Potassium Clavulanate Diluted 62.5 mg26 Amoxycillin + Dicloxacillin + Serratiopeptidase27 Amoxycillin + Tinidazole28 Ascorbic Acid + Manadione Sodium Bisulphate + Rutin + Dibasic Calcium

Phosphate + Adrenochrome mono Semicarbazone29 Atorvastatin + Vitamin D3 + Folic Acid + Vitamin B12 + Pyridoxine30 Azithromycin + Acebrophylline31 Azithromycin + Ambroxol32 Azithromycin + Cefixime33 Azithromycin + Cefpodoxime34 Azithromycin + Levofloxacin35 Azithromycin + Ofloxacin36 Azithromycin, Secnidazole and Fluconazole37 Beclomethasone + Clotrimazole + Chloramphenicol + Gentamycin + Lignocaine

Ear drops38 Beclomethasone + Clotimazole + Neomycin + lodochlorohydroxyquinone39 Beclomethasone + Clotrimazole + Gentamicin + lodochlorhydroxyquinoline40 Beclomethasone Diproprionate + Neomycin + Tolnaftate +

lodochlorhydroxyquinoline + Chlorocresol41 Benfotiamine + Metformin42 Benzoxonium Chloride + Lidocaine43 Betahistine + Ginkgo Biloba Extract + Vinpocetine + Piracetam

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44 Betamethasone + Fusidic Acid + Gentamycin + Tolnaftate + lodochlorhydroxyquinoline (ICHQ)

45 Betamethasone + Gentamicin + Tolnaftate + lodochlorhydroxyquinoline46 Betamethasone + Gentamycin + Zinc Sulphate + Clotrimoazole + Chlorocresol47 Betamethasone + Neomycin + Tolnaftate + lodochlorohydroxyquinoline +

Cholorocresol48 Borax + Boric Acid + Naphazoline + Menthol + Camphor + Methyl Hydroxy

Benzoate49 Bromhenxine + Phenylephrine + Chlorpheniramine + Paracetamol50 Bromhexine + Cetrizine + Phenylephrine IP+Guaifenesin + Menthol51 Bromhexine + Dextromethorphan52 Bromhexine + Dextromethorphan + Ammonium Chloride + Menthol53 Bromhexine + Dextromethorphan + Phenylephrine + Menthol54 Bromhexine + Phenylephrine + Chlorepheniramine Maleate55 Caffeine + Paracetamol + Chlorpheniramine56 Caffeine + Paracetamol + Phenylephrine + Cetirizine57 Caffeine + Paracetamol + Phenylephrine + Chlorpheniramine58 Calcium Gluconate + Chlorpheniramine + Vitamin C59 Calcium Gluconate + Levocetirizine60 Cefixime + Levofloxacin61 Cefixime + Linezolid62 Cefpodoxime Proxetil + Levofloxacin63 Cefuroxime + Linezolid64 Cephalexin + Neomycin + Prednisolone65 Certirizine + Phenylephrine + Paracetamol + Caffeine + Nimesulide66 Cetirizine + Acetaminophen + Dextromethorphan + Phenyephrine + Zinc

Gluconate67 Cetirizine + Ambroxol + Guaiphenesin + Ammonium Chloride + Phenylephrine +

Menthol68 Cetirizine + Dextromethorphan + Ambroxol69 Cetirizine + Dextromethorphan + Bromhexine + Guaifenesin70 Cetirizine + Dextromethorphan + Phenylephrine + Tulsi71 Cetirizine + Dextromethorphan + Phenylephrine + Zinc Gluconate + Paracetamol +

Menthol72 Cetirizine + Dextromethorphan + Zinc Gluconate + Menthol73 Cetirizine + Diethyl Carbamazine74 Cetirizine + Phenylephrine + Dextromethorphan + Menthol75 Cetirizine + Phenylephrine + Paracetamol + Ambroxol + Caffeine76 Cetirizine + Phenylephrine + Paracetamol + Zinc Gluconate77 Cetirizine + Nimesulide + Phenylephrine78 Chlopheniramine Maleate + Codeine Syrup79 Chloramphenicol + Beclomethasone + Clomitrimazole + Lignocaine80 Chloramphenicol + Lignocaine + Betamethasone + Clotrimazole + Ofloxacin +

Antipyrine81 Chlorpheniramine + Ammonium Chloride + Sodium Chloride82 Chlorpheniramine + Ammonium Chloride + Chloroform + Menthol83 Chlorpheniramine + Ammonium Chloride + Noscapine + Sodium Citrate84 Chlorpheniramine + Codeine + Sodium Citrate + Menthol Syrup

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85 Chlorpheniramine + Codeine Phosphate + Menthol Syrup86 Chlorpheniramine + Dextromethorphan + Phenylephrine + Paracetamol87 Chlorpheniramine + Paracetamol + Pseudoephedrine + Caffeine88 Chlorpheniramine + Phenylephrine + Caffeine89 Chlorpheniramine + Phenylephrine + Dextromethophan + Menthol90 Chlorpheniramine + Phenylephrine + Paracetamol + Zink Gluconate91 Chlorpheniramine + Terpin + Antimony Potassium Tartrate + Ammonium Chloride

+ Sodium Citrate + Menthol92 Chlorpheniramine + Vasaka + Tolubalsm + Ammonium Chloride + Sodium Citrate

+ Menthol93 Chlorpheniramine + Vitamin C94 Chlorpheniramine Maleate + Ammonium Chloride + Sodium Citrate95 Chlorpheniramine Maleate + Dextromethorphan + Dextromethophan +

Guaiphenesin + Ammonium Chloride + Menthol96 Chlorpheniramine+Ammonium Chloride + Menthol97 Chlorpromazine + Trihexyphenidyl98 Chromium Polynicotinate + Metformin99 Cilnidipine + Metoprolol Succinate + Metoprolol Tartrate100 Ciprofloxacin + Fluocinolone + Clotrimazole + Neomycin + Chlorocresol101 Ciprofloxacin + Fluticasone + Clotrimazole + Neomycin102 Ciprofloxacin + Phenazopyridine103 Clidinium + Paracetamol + Dicyclomine + Activated Dimethicone104 Clindamycin + Clotrimazole + Lactic Acid Bacillus105 Clindamycin + Telmisartan106 Clobetasol + Gentamicin + Tolnaftate + lodochlorhydroxyquinone + Ketoconazole107 Clobetasol + Neomycin + Miconazole + Clotrimazole108 Clobetasol + Neomycin + Miconazole + Zinc Sulphate109 Clobetasol + Ofloxacin + Ketoconazol + Zinc Sulphate110 Clobetasol + Ofloxacin + Miconazole + Zinc Sulphate111 Clobetasol Propionate + Ofloxacin + Ornidazole + Terbinafine112 Clobetasole + Gentamicin + Miconazole + Zinc Sulphate113 Clomifene Citrate + Ubidecarenone + Zinc + Folic Acid + Methylcobalamin +

Pyridoxine + Lycopene + Selenium + Levocarnitine Tartrate + L-Arginine114 Clotrimazole + Beclomethasone + Lignocaine + Ofloxacin + Acetic Acid + Sodium

Methyl Paraben + Propyl Paraben115 Clotrimazole + Beclomethasone + Ofloxacin + Lignocaine116 Clotrimazole + Ofloxacin + Lignocaine + Glycerine and Propylene Glycol117 Codeine + Chlorpheniramine + Alcohol Syrup118 Codeine + Levocetirizine + Menthol119 Cyproheptadine + Thiamine120 Dextromethorphan + Chlopheniramine + Ammonium + Sodium Citrate + Menthol121 Dextromethophan + Chlopheniramine + Bromhexine122 Dextromethophan + Chlorpheniramine + Guaifenesin + Ammonium Chloride123 Dextromethorphan + Ambroxol + Ammonium Chloride + Chlorpheniramine +

Menthol124 Dextromethorphan + Ambroxol + Guaifenesin + Phenylephrine +

Chlorpheniramine125 Dextromethorphan + Bromhexine + Guaiphenesin

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126 Dextromethorphan + Bromhexine + Guaiphenesin + Menthol127 Dextromethorphan + Cetirizine128 Dextromethorphan + Cetirizine + Guaifenesin + Ammonium Chloride129 Dextromethorphan + Chlorpheniramine + Chlorpheniramine Maleate130 Dextromethorphan + Chlorpheniramine + Guaiphenesin131 Dextromethorphan + Levocetirizine + Phenylephrine + Zinc132 Dextromethorphan + Paracetamol + Cetirizine + Phenylephrine133 Dextromethorphan + Phenylephrine + Ammonium Chloride + Menthol134 Dextromethorphan + Phenylephrine + Bromhexine + Guaifenesin +

Chlorpheniramine135 Dextromethorphan + Phenylephrine + Cetirizine + Paracetamol + Caffeine136 Dextromethorphan + Phenylephrine + Cetirizine + Zinc + Menthol137 Dextromethorphan + Phenylephrine + Guaifenesin + Certirizine + Acetaminophen138 Dextromethorphan + Phenylephrine + Guaifenesin + Triprolidine139 Dextromethorphan + Phenylephrine + Triprolidine + Menthol140 Dextromethorphan + Phenylephrine + Zinc Gluconate + Menthol141 Dextromethorphan + Triprolidine + Phenylephrine142 Dextromethorphan + Triprolidine + Phenylephrine143 Dextromethorphan + Bromhexine + Chlorpheniramine Maleate + Guaiphenesin144 Dextromethorphan + Promethazine145 Diclofenac + Paracetamol + Chlorpheniramine Maleate + Magnesium Trisillicate146 Diclofenac + Paracetamol + Chlorzoxazone+Famotidine147 Diclofenac + Paracetamol + Magnesium Trisilicate148 Diclofenac + Paracetamol injection149 Diclofenac + Tramadol + Chlorzoxazone150 Diclofenac + Tramadol + Paracetamol151 Diclofenac + Zinc Carnosine152 Dicyclomine + Paracetamol + Domperidone153 Diethyl Carbamazine + Chlorpheniramine + Guaifenesin154 Diethylcarbamazine Citrate + Cetirizine + Guaiphenesin155 Diethylcarbamazine + Cetirizine + Ambroxol156 Diphenhydramine + Guaifenesin + Bromhexine + Ammonium Chloride + Menthol157 Diphenhydramine + Guaiphenesin + Ammonium Chloride + Bromhexine158 Diphenhydramine + Terpin + Ammonium Chloride + Sodium Chloride + Menthol159 Diphenoxylate + Atropine + Furazolidone160 Disodium Hydrogen Citrate + Paracetamol161 Doxycycline + Serratiopeptidase162 Doxylamine + Pyridoxine + Mefenamic Acid + Paracetamol163 Dried Aluminium Hydroxy Gel + Prophantheline + Diazepam164 Dried Aluminium Hydroxy Gel + Prophantheline + Diazepam165 Drotaverine + Clidinium + Chlordiazepoxide166 Enrofloxacin + Bromhexine167 Ergotamine Tartrate + Belladonna Dry Extract + Caffeine + Paracetamol168 Ethylmorphine + Noscapine + Chlorpheniramine169 Famotidine + Oxytacaine + Magaldrate170 Fluconazole Tablet, Azithromycin Tablet and Ornidazole Tablets171 Flunarizine + Paracetamol + Domperidone

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172 Flupentixol + Escitalopram173 Furazolidone + Metronidazole + Loperamide174 Gabapentin + Mecobalamin + Pyridoxine + Thiamine175 Gentamicin Sulphate + Clotrimazole + Betamethasone + Lignocaine176 Gentamycin + Dexamethasone + Chloramphenicol + Tobramycin + Ofloxacin177 Glibenclamide + Metformin (SR)+ Pioglitazone178 Gliclazide 40mg + Metformin 400mg179 Gliclazide 80 mg + Metformin 325 mg180 Glimepiride + Pioglitazone + Metformin181 Glimepiride 1mg/2mg/3mg + Pioglitazone 15mg/15mg/15mg + Metformin

1000mg/1000mg/1000mg182 Glimepiride 1mg/2mg+ Pioglitazone 15mg/15mg + Metformin 850mg/850mg183 Glipizide 2.5mg + Metformin 400 mg184 Glucosamine + Methyl Sulfonyl Methane + Vitamin D3 + Manganese + Boron +

Copper + Zinc185 Guaifenesin + Bromhexine + Chlorpheniramine + Paracetamol186 Guaifenesin + Bromhexine + Chlorpheniramine + Phenylephrine + Paracetamol +

Serratiopeptidase (as enteric coated granules) 10000 SP Units187 Guaifenesin + Dextromethorphan188 Guaifenesin + Diphenhydramine + Bromhexine + Phenylephrine189 Heparin + Diclofenac190 Imipramine + Chlordiazepoxide + Trifluoperazine + Trihexyphenidyl191 Imipramine + Diazepam192 Ketoconazole + Tea Tree oil + Allantoin + Zinc Oxide + Aloe Vera + Jojoba oil +

Lavender oil + Soa noodles193 Ketotifen + Cetirizine194 Ketotifen + Levocetirizine195 Ketotifen + Theophylline196 L-5-Methyltetrahydrofolate Calcium + Escitalopram197 L-Arginine + Sildenafil198 Levocetirizine + Ambroxol + Phenylephrine + Guaiphenesin199 Levocetirizine + Ambroxol + Phenylephrine + Paracetamol200 Levocetirizine + Dextromethorphan + Zinc201 Levocetirizine + Montelukast + Acebrophylline202 Levocetirizine + Paracetamol + Phenylephrine + Caffeine203 Levocetirizine + Phenylephrine + Ambroxol + Guaiphenesin + Paracetamol204 Levocetirizine + Ranitidine205 Levofloxacin + Bromhexine206 Levofloxacin + Ornidazole + Alpha Tocopherol Acetate207 Levothyroxine + Pyridoxine + Nicotinamide208 Levothyroxine + Pyridoxine + Nicotinamide209 Lignocaine + Clotrimazole + Ofloxacin + Beclomethasone210 Lornoxicam + Paracetamol + Serratiopeptidase211 Lornoxicam + Paracetamol + Tramadol212 Lornoxicam + Paracetamol + Trypsin213 Magaldrate + Famotidine + Simethicone214 Magaldrate + Papain + Fungal Diastase + Simethicone215 Magaldrate + Ranitidine + Pancreatin + Domperidone

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216 Mebeverine & Inner HPMC capsule (Streptococcus Faecalis + Clostridium butyricum + Bacillus mesentricus + Lactic Acid Bacillus)

217 Menthol + Anaesthetic Ether218 Metformin (SR) 500mg + Pioglitazone 5mg219 Metformin (Sustained Release) 500mg + Pioglitazone 15 mg + Glimepiride 3mg220 Metformin + Atorvastatin221 Metformin + Bromocriptine222 Metformin + Gliclazide + Chromium Polynicotinate223 Metformin + Gliclazide + Pioglitazone + Chromium Polynicotinate224 Metformin + Glimepiride + Methylcobalamin225 Metformin 1000/1000/500/500mg + Pioglitazone 7.5/7.5/7.5/7.5mg + Glimepiride

1/2/1/2mg226 Metformin 500mg/500mg+Gliclazide SR 30mg/60mg + Pioglitazone 7.5mg/7.5mg227 Metformin 850mg + Pioglitazone 7.5 mg + Glimepiride 1mg228 Metformin 850mg + Pioglitazone 7.5 mg + Glimepiride 2mg229 Metformin ER + Gliclazide MR + Voglibose230 Metronidazole + Norfloxacin231 Metronidazole + Tetracycline232 N-Acetyl Cysteine + Ambroxol + Phenylephrine + Levocetirizine233 Naphazoline + Carboxy Methyl Cellulose + Menthol + Camphor + Phenylephrine234 Naphazoline + Chlorpheniramine + Zinc Sulphate + Boric Acid + Sodium Chloride

+ Chlorobutol235 Naproxen + Paracetamol236 Neomycin + Doxycycline237 Nimesulide + Certirizine + Phenylephrine238 Nimesulide + Cetirizine + Caffeine239 Nimesulide + Diclofenac240 Nimesulide + Dicyclomine241 Nimesulide + Loratadine + Phenylephrine + Ambroxol242 Nimesulide + Paracetamol + Cetirizine + Phenylephrine243 Nimesulide + Paracetamol + Levocetirizine + Phenylephrine + Caffeine244 Nimesulide + Paracetamol dispersible tablets245 Nimesulide + Paracetamol injection246 Nimesulide + Paracetamol Suspension247 Nimesulide + Phenylephrine + Caffeine + Levocetirizine248 Nimesulide + Pitofenone + Fenpiverinium + Benzyl Alcohol249 Nimesulide + Serratiopeptidase250 Nimesulide + Tizanidine251 Nimorazole + Ofloxacin252 Norfloxacin+ Metronidazole + Zinc Acetate253 Ofloxacin + Ornidazole Suspension254 Ofloxacin + Clotrimazole + Betamethasone + Lignocaine255 Ofloxacin + Metronidazole + Zinc Acetate256 Ofloxacin + Nitazoxanide257 Ofloxacin + Ornidazole + Zinc Bisglycinate258 Olmesartan + Hydrochlorothiazide + Chlorthalidone259 Omeprazole + Paracetamol + Diclofenac260 Oxytacaine + Magaldrate + Famotidine

Dissertation Report 17

261 Pantoprazole (as Enteric Coated Tablet) + Zinc Carnosine (as Film Coated Tablets)262 Paracetamol + Ambroxol + Phenylephrine + Chlorpheniramine263 Paracetamol + Bromhexine + Phenylephrine + Chlorpheniramine + Guaifenesin264 Paracetamol + Caffeine + Codeine265 Paracetamol + Cetirizine + Caffeine266 Paracetamol + Chlorpheniramine + Ambroxol + Guaifenesin + Phenylephrine267 Paracetamol + Codeine + Chlorpheniramine268 Paracetamol + Dextromethorphan + Bromhexine + Phenylephrine +

Diphenhydramine269 Paracetamol + Dextromethorphan + Chlorpheniramine270 Paracetamol + Diclofenac + Famotidine271 Paracetamol + Disodium Hydrogen Citrate + Caffeine272 Paracetamol + DL Methionine273 Paracetamol + Domperidone + Caffeine274 Paracetamol + Levocetirizine + Phenylephrine + Zink Gluconate275 Paracetamol + Levocetirizine + Pseudoephedrine276 Paracetamol + Loratadine + Dextromethophan + Pseudoephedrine + Caffeine277 Paracetamol + Loratadine + Phenylephrine + Dextromethorphan + Caffeine278 Paracetamol + Mefenamic Acid + Ranitidine + Dicyclomine279 Paracetamol + Pheniramine280 Paracetamol + Phenylephrine + Caffeine281 Paracetamol + Phenylephrine + Chlorpheniramine + Dextromethorphan + Caffeine282 Paracetamol + Phenylephrine + Chlorpheniramine + Zinc Gluconate283 Paracetamol + Phenylephrine + Desloratadine + Zinc Gluconate + Ambroxol284 Paracetamol + Phenylephrine + Levocetirizine + Caffeine285 Paracetamol + Phenylephrine + Triprolidine286 Paracetamol + Phenylephrine + Triprolidine + Caffeine287 Paracetamol + Prochlorperazine288 Paracetamol + Prochlorperazine Maleate289 Paracetamol + Promethazine290 Paracetamol + Propyphenazone + Caffeine291 Paracetamol + Pseudoephedrine + Cetrizine292 Paracetamol + Pseudoephedrine + Dextromethorphan + Cetirizine293 Paracetamol + Tapentadol294 Paracetamol + Phenylephrine + Levocetirizine + Sodium Citrate295 Paracetamol + Pseudoephedrine + Certirizine + Caffeine296 Permethrin + Cetrimide + Menthol297 Phenylbutazone + Sodium Salicylate298 Phenylephrine + Chlorpheniramine + Paracetamol + Bromhexine + Caffeine299 Phenytoin + Phenobarbitone300 Pholcodine + Phenylephrine + Promethazine301 Pholcodine + Promethazine302 Pioglitazone 15mg + Metformin 850 mg303 Pioglitazone 30 mg + Metformin 500 mg304 Pioglitazone 7.5/7.5mg + Metformin 500/1000mg305 Pseudoephedrine + Bromhexine306 Pseudoephedrine + Dextromethorphan + Cetirizine

Dissertation Report 18

307 Rabeprazole + Diclofenac + Paracetamol308 Rabeprazole + Zinc + Domperidone309 Rabeprazole + Zinc Carnosine310 Ranitidine + Domperidone + Simethicone311 Ranitidine + Magaldrate312 Ranitidine + Magaldrate + Simethicone313 Roxithromycin + Serratiopeptidase314 Salbutamol + Bromhexine315 Salbutamol + Bromhexine + Guaiphenesin + Menthol316 Salbutamol + Certirizine + Ambroxol317 Salbutamol + Choline Theophyllinate + Ambroxol318 Salbutamol + Choline Theophyllinate + Carbocisteine319 Salbutamol + Hydroxyethyltheophylline (Etofylline) + Bromhexine320 Serratiopeptidase (enteric coated 20000 units) + Diclofenac Potassium & 2 tablets

of Doxycycline321 Sildenafil + Estradiol Valerate322 Tamsulosin + Diclofenac323 Telmisartan + Metformin324 Terbutaline + Ambroxol + Guaiphenesin + Zinc + Menthol325 Terbutaline + Bromhexine + Etofylline326 Terbutaline + Bromhexine + Guaiphenesin + Dextromethorphan327 Terbutaline + Etofylline + Ambroxol328 Terbutaline + N-Acetyl L-Cysteine + Guaifenesin329 Terpinhydrate + Dextromethorphan + Menthol330 Thyroid + Thiamine + Riboflavin + Pyridoxine + Calcium Pantothenate +

Tocopherol Acetate + Nicotinamide331 Thyroxine + Pyridoxine + Folic Acid332 Tranexamic Acid + Proanthocyanidin333 Ursodeoxycholic Acid + Silymarin334 Voglibose + Pioglitazone + Metformin335 Voglibose+ Metformin + Chromium Picolinate336 Zinc Carnosine + Magnesium Hydroxide + Dried Aluminium Hydroxide +

Simethicone337 Zinc Carnosine + Oxytacaine338 Zinc Carnosine + Sucralfate

Large sales volumes of FDCs in India, in comparison to Britain and United States of America, have been deliberated upon by expert committees since the 1980s and bans on various combinations have periodically been issued.

In 2015, a study of FDCs in four therapeutic areas demonstrated that there were multiple formulations available on the Indian market that had been banned, restricted or never approved internationally. Ideally, then, CDSCO ought to be able to make out a strong case upholding its ban. Case law on similar bans would appear to bear this out.

The Central government imposes such bans by exercising its powers under Section 26A of the Drugs and Cosmetics Act, 1940. This provision allows the government to prohibit the

Dissertation Report 19

manufacture, sale or distribution of drugs that are likely to pose a risk to human beings or animals, or that do not have the therapeutic value that they claim, or contain ingredients in quantities for which there is no therapeutic justification. The Central government must also be satisfied that it is necessary or expedient in the public interest to impose such prohibition.

Dissertation Report 20

2.0 Literature Review.

Drugs undergo rigorous testing before they are introduced into the market. The efficacy as well as safety profiles of the drug are tested. In spite of this, some adverse effects of drugs appear only after the drug is released called Pharmacovigilance.

Pharmacovigilance is the Pharmacological science relating to the detection, assessment understanding and prevention of adverse effects, particularly, long-term and short-term side-effects of medicines.

DCGI (Drug Controller general of India) is the highest authority in India to expand the approval of any drug or to ban a drug. If any is to have harmful side-effects, the government issues the ban order and all manufacturer and wholesaler are asked not to manufacture and sell the particular medicine.

Dissertation Report 21

If doctors stop prescribing drugs that are harmful to patient’s health, chemists will automatically stop selling since there are no patients asking for it, and hence, manufacturers do not produce it. Certainly, much of the problem can be solved like that the manufacturers have every reason to sell their products if there are buyers.

Here is the list of companies and their products that are affected

S. No. Company Brand Name of Medicine

1. Abbott Phensedyl, Tossex, Tribet

2. Alkem Sumo, Taxim AZ

3. Cipla Triexer & Oflox

4. Glenmark Ascoril

5. GSK Crocin Cold & FLU Max

6. Ipca Zerodol P

7. Lupin Gluconorm

8. Macleods Panderum Plus

9. Mankind Paediatric syrup T-98 TedyKoff

10. Medley Pharmaceuticals O2

11. Micro Labs Dolo Cold

12. Panacea Biotech Nimulid

13. Paras Lab D Cold-Total

14. Pfizer Corex

15. Procter and Gamble Vicks Action 500 Extra

16. Sun Pharma Gemer P, Chericof, Decoff

17. Torque Pharma Kofnil

18. Wockhardt Zedex, Ace Proxyvan

FDC Drugs in Indian LawFDCs should always be based on convincing therapeutic justification. Each FDC should be carefully justified and clinically relevant (e.g., in cases when each component of the FDC has several possible dosages, dosages that have shown benefit on clinical outcomes may be preferable).

Appendix VI of Schedule Y (Drugs and Cosmetics Rules 1945) specifies the requirements for approval for marketing of various types of FDCs. The same is further elaborated to provide a detailed guidance for industry.

Drug control issues in India

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The Indian drug control authority has issued notifications banning many FDCs. The principal notification under Section 26-A of the Drugs and Cosmetics Act, 1940, (prohibiting manufacture, sale and distribution of certain FDCs, which do not have any therapeutic justification or are likely to involve risk to the human being) banned 79-drug formulations from the year 1983 till date. Some examples are FDCs of vitamins with anti-inflammatory agents and tranquillizers, of anti-histamines with anti-diarrheal etc. It is an accepted fact that an FDC be treated as a new drug, because by combining two or more drugs, the safety, efficacy, and bioavailability of the individual active pharmaceutical ingredient (API) may change. As per the Drugs and Cosmetic Act, 1940, any new drug and the permission to market a drug is to be given by the Drugs Controller General of India (DCGI). As per rule 122 (E) of the Drugs and Cosmetic Rules, 1945, the same criteria holds good for US markets as well.

FDCs in India More than one-third of all the new drug products introduced worldwide during the last decade were FDC preparations. The trend varied from country to country. In Japan, only 10% of the new products were fixed ration combinations, whereas, in European countries like Spain, it was up to 56%. However, such statistical data are lacking for the developing countries, although, the trend seems to be the production and prescription of FDCs. The World Health Organization (WHO) lists nearly 325 essential drugs, including only 19 of such drug combinations. Whereas, the national list of essential medicines has 354 essential drugs, including 14 drug combinations. FDCs available for the treatment of various ailments range from nutritional deficiency to cardiovascular diseases. Maximum FDC preparations comprise vitamins, cough suppressants, anti-diarrheal, iron preparations, antacids, analgesics, and tonics [18].

There are many popular FDCs in the Indian pharmaceutical market, which have flourished in the last few years. Medical experts world over have been expressing serious concerns over the marketing of increasing number of drug combinations by pharmaceutical companies, particularly in the developing countries. Some FDCs can impose unnecessary financial burden, increased adverse effects, as well as hospitalization, and decreased quality of life.

The Indian drug control authority has issued notifications banning many FDCs. The principal notification under Section 26-A of the Drugs and Cosmetics Act, 1940, (prohibiting manufacture, sale and distribution of certain FDCs, which do not have any therapeutic justification or are likely to involve risk to the human being) banned 79 drug formulations from the year 1983 till date. Some examples are FDCs of vitamins with anti-inflammatory agents and tranquillizers, of anti-histamines with anti-diarrheal etc.

The DCGI had given marketing approvals for 40 FDCs in January 2002. It is an accepted fact that an FDC be treated as a new drug, because by combining two or more drugs, the safety, efficacy, and bioavailability of the individual API may change. As per the Drugs and Cosmetic Act, 1940, any new drug and the permission to market a drug is to be given by the DCGI. As per rule 122 (E) of the Drugs and Cosmetic Rules, 1945, the same criteria holds good for US markets as well. WHO has made the following observations regarding the FDCs, as new fixed ratio combination products are regarded as new drugs in their own right [18].

FDCs are highly popular in the Indian pharmaceutical market and have been particularly flourishing in the last few years. The rationality of FDCs should be based on certain aspects such as:

• The drugs in the combination should act by different mechanisms • The pharmacokinetics must not be widely different

Dissertation Report 23

• The combination should not have supra-additive toxicity of the ingredients.

Most FDCs have the following demerits:

• Dosage alteration of one drug is not possible without alteration of the other drug • Differing pharmacokinetics of constituent drugs pose the problem of frequency of

administration of the formulation • By simple logic, there are increased chances of adverse drug effects and drug

interactions compared with both drugs given individually.

The “combined” pills are marketed with slogans like “ibuprofen for pain and paracetamol for fever” and “ibuprofen for peripheral action and paracetamol for the central action.” It is indeed very unfortunate that the medical fraternity in India has fallen prey to such gimmicks. The gullible patient then has to pay for the doctor’s complacence in terms of extra cost and extra adverse effects. There is no synergism when two drugs acting on the same enzyme are combined. Thus combining two NSAIDs does not and cannot improve the efficacy of treatment. It only adds to the cost of therapy and more importantly, to the adverse effects and the ‘muscle relaxants’ in some of these combinations are of questionable efficacy.

Combinations of NSAIDs/analgesics with antispasmodic agents are also available in India. They are not only irrational but also could be dangerous. The antipyretic drug promotes sweating and thereby helps in heat dissipation. On the other hand, the anticholinergic antispasmodic drug inhibits sweating. Combining these two can result in dangerous elevation of the body temperature. Some such fixed drug combinations are now banned in India.

Medical fraternity in India has fallen prey to such gimmicks. The gullible patient then has to pay for the doctor’s complacence in terms of extra cost and extra adverse effects. There is no synergism when two drugs acting on the same enzyme are combined. Thus combining two NSAIDs does not and cannot improve the efficacy of treatment. It only adds to the cost of therapy and more importantly, to the adverse effects and the ‘muscle relaxants’ in some of these combinations are of questionable efficacy.

Combinations of NSAIDs/analgesics with antispasmodic agents are also available in India. They are not only irrational but also could be dangerous. The antipyretic drug promotes sweating and thereby helps in heat dissipation. On the other hand, the anticholinergic antispasmodic drug inhibits sweating. Combining these two can result in dangerous elevation of the body temperature. Some such fixed drug combinations are now banned in India.

Fixed-dose combination drugs like Zimnic AZ aren’t unique to India. They are used worldwide to improve patients’ compliance in complicated courses of treatment for such conditions as HIV, tuberculosis and malaria. It’s easier to get patients to take one drug than a number of different pills.

A study published in the journal of Public Library of Science (PLOS) in May found that over 70% of non-steroidal anti-inflammatory drug (NSAID) combinations, which are used as painkillers, were being marketed in India without central government approval. The authors recommended that unapproved drug combinations be banned immediately.

Combination drugs are also useful in increasing compliance among the many Indian patients who can’t read, said Sanjay Sikaria, director of drugmaker Suncare Formulations Private Ltd in Uttarakhand state. “FDCs are not bad,” he said. “Rampant misuse of these drugs is bad.”

Dissertation Report 24

That’s the problem in India, where there has been an explosion of combination drugs. They have become a way to boost sales and increase market share: More and more companies have tacked on ingredients to existing drugs so they can peddle a new product to doctors and chemists, say people in the country’s highly competitive pharmaceutical sector.

Combination drugs are profitable because of high demand from doctors, who see them as a way to ensure patient compliance, say people in the pharmaceutical industry. Many doctors also see them as providing “quick-fix solutions” that cover multiple possible symptoms with a single pill, said a physician employed by a pharmaceutical company. “The market needs it and demands it,” he said. 

Between 2011 and 2014, India’s fixed-dose combination market grew more than 40% in Rupee terms, according to IMS Health.

3.0 Justification

The Central Drugs Standard Control Organization (CDSCO) in India has banned the manufacture and sale of more than 300 fixed dose drug combination to prevent the misuse of drugs and to prevent drug resistance.A gazette notification by Ministry of Health and Family Welfare was issued on 10 th March 2016 to ban these fixed drug combinations. The list includes common cough syrup solutions, analgesics and antibiotic combinations. Some of these drugs are sold over the counter. In 2014 a committee was set up to review over 6000 drug combinations that had entered the

Dissertation Report 25

market based only on state regulator’s approval.

This ban is likely to affect many leading pharmaceutical drug manufacturers such as Pfizer, Abbott, Macleods Pharma and Glenmark Pharmaceuticals. Some of these companies have already appealed to the court and received interim injunctions.

This could be a ‘Maggie moment’ for the big pharma companies as the Govt. has ordered stay on the ban of FDC drugs for several companies.

Due to this ban pharma companies are suffering huge financial losses. The BSE Healthcare index dropped, all the stock that was already manufactured and stored is now is valued zero. The study is important in the aspect of pharmaceutical market value, the reasons given by the CDSCO and the measures taken by the pharma companies.

4.0 Objectives1.0 Reason for ban on FDC drugs2.0 Financial loss endured by the pharma companies3.0 Measures taken by the pharma companies4.0 Impact on consumers

Dissertation Report 26

5.0 Research MethodologyResearch Design

An observational study was done on the recent ban on over 300 drugs to study its implications on the pharmaceutical market in India.

A cross sectional study was performed in which secondary data was studied, followed by its depth analysis.

Research Tools

Dissertation Report 27

A checklist was prepared keeping in view of the objectives. The data was collected from the secondary sources. A few published articles were also referred.Primary data was also collected, studied, analysed and consolidated to form the dissertation report.

Data Collection

The data was collected from few published journals, newspaper articles, websites, case studies and online organizational records.

Primary data was collected by interviewing five chemists in West Delhi. Questions were asked regarding the effect on daily sale of drugs after the ban, change in inventory management, change in prescription pattern and customer reviews.

Dissertation Report 28

6.0 Study Findings

Reason for the ban of FDC drugs

On March 10, the Central Drugs Standard Control Organisation (CDSCO)—an Indian drug regulator—banned 344 drugs in the country. The notification said that these drugs can’t be made, sold or distributed in the country. These medicines are fixed dose combinations, which mean they are made by mixing two or more drugs.

The CDSCO gave two main reasons for the ban: the drugs were “likely to involve risk to human beings” while safer alternatives were available, and they were “found to have no therapeutic justification.” The list of the banned drugs included some widely used products

Dissertation Report 29

such as the Vicks Action 500 tablet, made by Procter & Gamble, and Pfizer’s Corex cough syrup.

The Ministry, while banning over 300 drug combinations also said that “there are safer alternatives available in the market.” The Department said that it had the best of scientists on board to study the effects of these drugs. "We have tried to bring objectivity to the issue by roping in the best of scientists to study the effects," the Ministry said.

The order hasn't come out of the blue. The government says that the companies were first issued show cause notices and even given a chance to present their case, but some companies hadn't even bothered to respond to the notice.

After a thorough examination by the expert committee, the Central government said that it was satisfied with the recommendations of the expert committee.

According to doctors and health experts across the globe, the increasing use of combination drugs is dangerous since they cause antibiotic resistance in patients. Also, since most FDCs are common to many active ingredients, there's an alarming risk of difficulties to identify which medicine is responsible for the adverse effects, if any.

In 2014, India set up a committee to review more than 6,000 combinations that had entered the market based only on state regulators’ approval. Policymakers gave pharmaceutical companies a chance to retroactively prove the safety and efficacy of these drugs by submitting data on their drugs.

Uncertainties regarding the quality of FDC formulations and their registration, and barriers to effective implementation in national programs, have limited the widespread use of FDCs. Bioavailability of individual components may change when put into combination with other components. For example, variable bioavailability of the tuberculosis drug rifampicin from solid oral dosage forms has been reported, whereas bioavailability problems with the isoniazid, pyrazinamide and ethambutol components of FDCs have not been encountered, presumably because of the much greater water solubility and more rapid rates of absorption of these latter drugs. Hence, using FDC tablets with poor rifampicin bioavailability could lead directly to treatment failure and may encourage drug resistance. Other FDC components may have similar issues.

Now many of the combinations which are recently banned in India, they were already banned in many countries like USA, Canada, Europe. FDA has clearly mentioned various side effects of drugs in FDCs which are very harmful and can be fatal.

There are more than 300 FDCs which were banned; 338 to be precise. I have categorized them into their purpose of usage/type. The following is the Chart 1 which depicts the same:

Dissertation Report 30

Zinc SupplementSupplement

Stomach acheSkin infection

Sedative/HypnoticsProbiotic

NSAIDsMultivitamin

Melasma treatmentLiver Function

Joint PainGout Treatment

ExpectorantErectile Dysfunction

Burn TreatmentAntiulcer

AntithyroidAntiseptic

AntimigraineAntihypertensive+Antidiabetic

AntihypertensiveAntihelmentic

AntifungalAntiemetic

AntidiabeticAntidepressant

Anticoagulant+AnalgesicAntibiotic+Antiprotozoal

Antibiotic+AntihypertensiveAntibiotic+Antifungal

AntibioticAntiasthametic

AntianxietyAntiallergic+Analgesic

AntiallergicAntacid

Anaesthetic

0 10 20 30 40 50 60 70 80

14

1111

351111

259

21

51

211

32

134

264

13

119

2420

48

7011

1

Type of FDCs banned

Dissertation Report 31

Out of 338 FDCs banned, there are 70 antiallergic drugs, 59 expectorants, 33 analgesics/antipyretics, 26 antidiabetics, 24 antibiotics and 20 antiasthametics. Also there was one multivitamin and probiotic each which were strangely included in banned FDCs.

For further clarity, the following Chart 2 categorises or type of FDCs according to their usage in percentage of grand total:

Zinc SupplementSupplement

Stomach acheSkin infection

Sedative/HypnoticsProbiotic

NSAIDsMultivitamin

Melasma treatmentLiver Function

Joint PainGout Treatment

ExpectorantErectile Dysfunction

Burn TreatmentAntiulcer

AntithyroidAntiseptic

AntimigraineAntihypertensive+Antidiabetic

AntihypertensiveAntihelmentic

AntifungalAntiemetic

AntidiabeticAntidepressant

Anticoagulant+AnalgesicAntibiotic+Antiprotozoal

Antibiotic+AntihypertensiveAntibiotic+Antifungal

AntibioticAntiasthametic

AntianxietyAntiallergic+Analgesic

AntiallergicAntacid

Anaesthetic

0.00% 5.00% 10.00% 15.00% 20.00% 25.00%

0.30%1.19%

0.30%0.30%0.30%0.30%

10.42%0.30%0.30%0.30%0.30%0.60%

17.56%0.60%

0.30%1.49%

0.30%0.60%

0.30%0.30%

0.89%0.60%

3.87%1.19%

7.74%1.19%

0.30%0.89%

0.30%5.65%

7.14%5.95%

1.19%2.38%

20.83%3.27%

0.30%

Type of FDCs banned

Dissertation Report 32

Out of 338 banned FDCs, 20% are antiallergic, 17% are expectorants, about 10% are analgesics/antipyretics, 8% are antidiabetics and these all contribute more than 50% of banned FDCs.

Following graph represents various side effects of the FDCs which are mostly encountered by the patients:

Stomach upset

Ototoxicity+Allergic reaction

Ototoxicity

Other

Nephrotoxicity+CNS Problems

Nausea/Vomiting

Kindney problem+Gastric Problem

Joint pain+Headache

Hypoglycemia

Hepatotoxicty+Nephrotoxicity

Hepatotoxicty

Gastric problem+Muscular Pain

Gastric Problem+Hepatotoxicty

Gastric problem+CNS Problems

Gastric problem+Allergic Reactions

Gastric Problem

CVS+Muscular Pain

CNS Problems+Rheumatoid Arthritis

CNS Problems+Renal Calculi

CNS Problems+Ototoxicity

CNS Problems+Nephrotoxicity

CNS Problems+Muscular Pain

CNS Problems+Hypersensitivit

CNS Problems+Hepatotoxicity

CNS Problems+Gastric problem

CNS Problems+Cardiovascular Disease

CNS Problems+Blurry Vision

CNS Problems

Cardiovascular Disease+Muscular Pain

Cardiovascular Disease+Hepatotoxicty

Allergic Reactions+Gastric problem

Allergic Reactions+CNS Problems+Gastric problem

Allergic Reactions+CNS Problems

Allergic reactions

0 20 40 60 80 100 120 140

2

4

13

9

2

2

1

1

3

1

1

2

8

12

3

10

5

1

3

8

4

16

1

42

7

6

1

130

1

2

2

3

26

4

Dissertation Report 33

As you can see from the graph 1, maximum FDCs cause CNS (Central Nervous System) problems, severe allergic reactions and hepatotoxicity. The term “(blank)” represents the possible side effects of supplements and

For more clarity, the following chart 2 represents the percentage of side effects of various FDCs:

Dissertation Report 34

CNS Problems+Blurry Vision

CNS Problems+Hypersensitivit

Hepatotoxicty+Nephrotoxicity

CNS Problems+Rheumatoid Arthritis

Joint pain+Headache

Hepatotoxicty

Kindney problem+Gastric Problem

Cardiovascular Disease+Muscular Pain

Nephrotoxicity+CNS Problems

Gastric problem+Muscular Pain

Stomach upset

Allergic Reactions+Gastric problem

Nausea/Vomiting

Cardiovascular Disease+Hepatotoxicty

Gastric problem+Allergic Reactions

Allergic Reactions+CNS Problems+Gastric problem

Hypoglycemia

CNS Problems+Renal Calculi

Allergic reactions

CNS Problems+Nephrotoxicity

Ototoxicity+Allergic reaction

CVS+Muscular Pain

CNS Problems+Cardiovascular Disease

CNS Problems+Gastric problem

CNS Problems+Ototoxicity

Gastric Problem+Hepatotoxicty

Gastric Problem

Gastric problem+CNS Problems

Ototoxicity

CNS Problems+Muscular Pain

Allergic Reactions+CNS Problems

CNS Problems+Hepatotoxicity

CNS Problems

0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00% 35.00% 40.00% 45.00%

0.31%

0.31%

0.31%

0.31%

0.31%

0.31%

0.31%

0.31%

0.61%

0.61%

0.61%

0.61%

0.61%

0.61%

0.92%

0.92%

0.92%

0.92%

1.22%

1.22%

1.22%

1.53%

1.83%

2.14%

2.45%

2.45%

3.06%

3.67%

3.98%

4.89%

7.95%

12.84%

39.76%

% of Grand Total Side effects

From the above chart, we can interpret that out of 338 FDCs banned, more than 50% of the dugs causes CNS problems and hepatotoxicity. CNS problems include dizziness, vertigo and/or nausea/vomiting. This clearly shows that these FDCs should have been banned a long time ago.

Dissertation Report 35

Zimnic AZ (manufactured by Abbott) has been promoted for a wide array of indications such as fevers, colds, urinary tract infections and even sexually transmitted diseases. The drug is also said to be used by patients to prevent post-surgery infections and lung problems. Medical experts, however, said that this antibiotic combination is very risky and some indications, particularly that of colds, is not sound.

Clinicians and other health professionals say improper administration of antibiotic combinations may be adding up to the burden of antibiotic resistance in the country. In fact, superbugs or strains of pathogens that have grown resistant to antibiotics have been discovered among individuals who have travelled from India to nations such as Britain and the U.S.

India has banned the production and marketing of more than 300 fixed dose combinations (FDCs) drugs, including cough syrups like Phensedyl and Corex widely consumed by addicts in Bangladesh.

Bangladesh has long been urging India to stop the smuggling of Phensedyl and some of its officials had even suggested that production of these drugs be stopped.

The cough syrup is already banned in Bangladesh as its Codeine content is unusually high and attracts addicts, who cough up to three times the rate in India to buy these cough syrup bottles.

The Phensedyl smuggling volume ran into nearly 1.5 billion Indian rupees, according to most conservative estimates.

Financial Loss Endured by the Pharmaceutical Companies

The government notification issued March 10 by Union Health Ministry Joint Secretary KL Sharma said various combination drugs, after examination by an expert committee, were found to be risking the lives of humans. The committee had submitted its recommendations to the Central government on the prohibition of manufacture, sale and distribution of such drugs.

The Centre has ordered a ban on the manufacture, sale and distribution of such drugs under Section 26(A) of the Drugs and Cosmetics Act, 1940, the notification said.

In 2014, the government appointed an expert committee to review over 6,000 combination drugs which entered the market based only on state regulators' approval. The committee was supposed to classify the drugs into rational, irrational, and those that need further studies, Sharma was quoted by the Reuters as saying.

He said based on the responses from the committee and assessment of products, more than 300 drugs have been banned.

The annual impact of the ban, according to AIOCD (All Indian Origin Chemists & Distributors) Pharmasofttech AWACS (Airborne Warning And Control System) — a pharmaceutical market research firm, is estimated to be Rs 3,049 crore, affecting 3% of the retail pharma market.

Dissertation Report 36

The drug companies have recalled the banned products from stockists, retailers after the government in a notification dated March 10, directed a ban on various FDCs.

Stocks of impacted brands will need to be recalled and destroyed, and companies like Cipla, Emcure, Mankind and Zuventus on Tuesday started informing stockists and retailers about the banned drugs, asking them to stop selling them with immediate effect.

The sudden move has created confusion among stockists, retailers and patients, forcing certain companies like Abbott, Glenmark and Macleods to join Pfizer in challenging the ban in courts, even as the drug industry body, IDMA, said that it is weighing all options. They have been granted interim injunction suspending the implementation of the notification till the next date of hearing on March 21.

Taking the drug industry by surprise, the health ministry, in a notification issued on March 12, prohibited the manufacture, sale and distribution of 344 fixed-dose combinations (FDCs) with immediate effect. The drug industry along with stockists feel that sufficient time should have been given so that losses could have been reduced. In the past, the government issued similar notifications from a prospective date, giving the industry sufficient time to prepare, particularly for drugs which are not life-threatening

The drop in domestic revenue will only add to the woes of Indian drug-makers. Experts have already warned of a bleak export growth for the 2017 fiscal year. For instance, a Feb. 1 report by India Ratings and Research, a credit ratings agency, said export growth in the 2017 fiscal will be about 5%. The slow growth is due to regulatory challenges and competition in foreign markets. The agency expects the domestic market growth around 13-15%. Investors are worried as this ban means loss in revenue for pharma companies.

“As for the revenue, most Indian companies are dependent on combination drugs because they drive sales. So a drop in revenue could be possible for companies who are heavily dependent on combination drugs,” Surajit Pal, a pharma research analyst at Prabhudas Lilladhar, a brokerage, told Quartz.

Pal believes this ban was long due.

“Typically, around 60-70% of combination drugs in the industry do not hold any logic. Many of them are produced for purely commercial purposes, irrespective of what their health impacts are. These practices should be stopped,” he said.

The BSE Healthcare Index is down 9% so far this year.

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Earlier this month, Dinesh Thakur, a whistle-blower and activist, had filed public interest litigation against the CDSCO, questioning regulatory standards in India’s pharma industry. The Supreme Court dismissed the petition.

The government ban on fixed dose combination (FDC) drugs has taken a toll on pharmaceuticals stocks, which saw a fall in the range of 20-50% year-to-date. Marksans Pharma Ltd has fallen 47% in 2016 so far, while Wockhardt Ltd posted a decline of 38% in its share price. Pfizer Ltd, another company which got affected with the FDC ban, saw its shares fall 29% year-to-date. .

According to the latest data released by pharmaceutical research company AIOCD Pharmasofttech AWACS, Abbott Healthcare is likely to suffer a loss of Rs.485 crore, MacLeods Pharma of around Rs.370 crore and Pfizer to the tune of Rs.368 crore.

“This is a significant financial impact to companies. Some of the well-known brands have been included in the mix along with some truly irrational brands. The intention is good but the government will have to find a way to segregate the bad from the good,” said Sujay Shetty, leader - pharma life sciences, PWC India.

Pfizer India said that the prohibition of the Corex drug is likely to adversely impact the company’s revenue and profitability. Corex recorded sales of Rs.176 crore for the first nine months of the fiscal year ended on 31 December 2015. Pfizer said it was suspending the manufacturing and sale of its popular Corex cough syrup which contains a combination of Chlopheniramine Maleate and Codeine syrup. However, after moving the Delhi High Court over the order, the HC has provided interim relief to the company until the next hearing date which hasn't been announced yet. The company said the ban is likely to have an adverse

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impact on its revenue and profitability, and that it is exploring all the available options in this issue.

"A government of India notification, dated March 10, 2016, has prohibited the manufacture, sale and distribution of a fixed-dose combination of Chlopheniramine Maleate + Codeine Syrup with immediate effect. In view of this, the company has discontinued the manufacture and sale of its drug 'Corex' with immediate effect." the company said in a filing to the Bombay Stock Exchange (BSE).

Macleods Pharma's much sought skin cream Panderm+ has also been banned. This cream itself was bringing Rs 228.2 crore (Rs 2.28 billion) to the company in annual sales.

Mankind Pharma's 32 brands have been banned which had annual sales of Rs 234 crore (Rs 2.34 billion).

Abbott saw 36 of its brands banned which had annual sales of Rs 400 crore (Rs 4 billion) in the same period. Similarly, 30 brands by Macleods Pharma, with annual sales of Rs 400 crore, have been banned.

Abbott's three major cough syrups - Phensedyl, Tixylix and Tossex - which had annual sales of Rs 290 crore (Rs 2.9 billion), were also banned by the government.

Phensedyl (cough syrup), marketed by Abbott, takes up approximately one-third of the entire Indian cough syrup market. The sales of this medicine is said to contribute to more than 3 percent of the entire company revenue of $1 billion in India. The

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Health Ministry also included antibiotic combinations in the list of banned drugs. One product affected by the ban is Abbott's Zimnic AZ, which is a combination of cefixime and azithromycin. The shares of Abbott India Ltd fell by 21.4% year-to-date.

Abbott is not the only firm to manufacture such drug combination in India as about 15 more companies also produce this drug.

"Our concern is patients may not have access to some medicines which have been approved by the DCGI (Drug Controller General of India) and are being used safely and effectively in India for years," an Abbott official was quoted by the Economic Times as saying.

Market research agency PharmaTrac meanwhile was quoted as saying by ET that Abbott may take a hit of Rs 485 crore and Pfizer Limited a hit of Rs 368 crore as a result of the government move.

Sun Pharma - India's largest pharmaceutical company - has got its 28 brands banned which had total annual sales of just Rs 95.7 crore (Rs 957 million).

Lupin's anti-diabetic drug Gluconorm -PG, which had sales of Rs 46.5 crore (Rs 465 million), has also been banned.

This brand's FDC name is Glimepiride + Pioglitazone + Metformin. This FDC - which is sold by more than 85 companies under different brand names - had total sales of Rs 525 crore annually.

Chlopheniramine Maleate + Codeine, which had annual sales of Rs 700 crore (Rs 7 billion) and is sold by almost 60 companies in the country, has also been banned.

GlaxoSmithKline's four brands which have been banned are - Crocin Cold and Flu, Piriton-CS, Dilo-DX and Piriton Expect. These four drugs had annual sales of Rs 58 crore (Rs 580 million).

Following is a list of companies and there percentage of shares dropped after the ban:

S. No. Company % of Shares dropped after the ban1. Abbott 21.4

2. Alembic 28

3. Anuh Pharma 35

4. Aurobindo Pharma 17

5. Biocon 10

6. Cipla Ltd 19

7. Claris Lifesciences 36

8. Divi’s Laboratories Ltd 14

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9. Glenmark Pharmaceuticals 13

10. Ipca Laboratories 29

11. Lupin 10

12. Marksans Pharma Ltd 47

13. Merck Ltd 17

14. Nacto Pharma 19

15. Nector Lifesciences 28

16. Novartis India 19

17. Orchid Pharma 35

18. Pfizer India 29

19. Sequent Scientific 33

20. Sharon Bio Medicine Ltd 54

21. SMS Pharmaceuticals 31

22. Strides Shasun 20

23. Syncom Formulations India 50

24. Torrent Pharmaceuticals 10

25. Unichem Laboratories 18

26. Vimta Labs 35

27. Wockhardt Ltd 38

[Source: http://www.livemint.com/Money/HZJ4tIfRbWd8cyCfUouKtO/Pharma-stocks-dive-2055-this-year-after-ban-on-combination.html]

The same has been presented in form of a bar chart for more clarity:

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Wockhardt Ltd

Vimta Labs

Unichem Laboratories

Torrent Pharmaceuticals

Syncom Formulations India

Strides Shasun

SMS Pharmaceuticals

Sharon Bio Medicine Ltd

Sequent Scientific

Pfizer India

Orchid Pharma

Novartis India

Nector Lifesciences

Nacto Pharma

Merck Ltd

Marksans Pharma Ltd

Lupin

Ipca Laboratories

Glenmark Pharmaceuticals

Divi’s Laboratories Ltd

Claris Lifesciences

Cipla Ltd

Biocon

Aurobindo Pharma

Anuh Pharma

Alembic

Abbott

0 10 20 30 40 50 60

38

35

18

10

50

20

31

54

33

29

35

19

28

19

17

47

10

29

13

14

36

19

10

17

35

28

21.4

% of Shares dropped after the ban

Procter & Gamble has stopped the manufacturing and sale of Vicks Action 500 Extra which contains a combination of paracetamol, phenylephrine and caffeine.

"Our product 'Vicks Action 500 Extra' has the same fixed dose combination and gets covered under notification. We have discontinued the manufacture and sale of all SKUs of 'Vicks Action 500 Extra with immediate effect," the company said.

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He said some of the formulations in the combination drugs have been the treatment of choice in certain medical conditions.

The Indian Pharmaceutical market in FY12 stood at Rs. 63,000 cr - more than double than in FY07. This market is estimated to grow at 15% CAGR up to 2020 driven by lifestyle diseases such as cardiovascular, diabetics and Oncology as has been the case in the past. FDC has grown its domestic revenues by 60% over FY07-FY12 while the market has doubled due to lack of strong brands in these fast growing segments. Market share is down to 1.2% from almost 1.5% in FY07. We expect FDC’s domestic business to grow at higher single digits given stiff competition from MNC and leading domestic players.

Measures Taken by Pharma Industries

The Drugs Controller General of India (DCGI) Dr G N. Singh’s recent act of banning of more than 300 FDCs under Rule 26-A of Drugs and Cosmetics Act (D&C Act) with immediate effect, without allowing the pharma companies any chance to sell the already manufactured products which are in the market, is injudicious, imprudent and unfair as far as the Indian pharma industry and the country’s patient society are concerned, said the Indian Drug Manufacturers Association (IDMA).

Some of the common household medicines, including Crocin Cold and Flu, D-Cold Total, Nasivion, Sumo, Oflox, Gastrogyl, Chericof, Nimulid, Kofnil, Dolo, Decoff, O2, paediatric syrup T-98 and TedyKoff, have been banned by the Indian government as part of its decision to halt the manufacture and sale of fixed dose combinations (FDCs).

Many of these drugs are cleared or licensed officially by the state licensing authorities under the Drugs and Cosmetics Act and also by the office of the DCGI. Further, these medicines are prescribed to the patients by thousands of qualified doctors, and no adverse reaction has been reported either of efficacy or of safety.

According to him, Dr G N Singh has not only given any opportunity to the industry for personal hearing, but also not responded to the many issues raised by manufacturers in their reply to his show-cause notices. He said in the past government had withdrawn 94 products, and the whole exercise was carried out in a systematic, careful and judicious manner so as to avoid hardship to all concerned.

The drug companies said the ban has taken them by surprise as they were not informed and consulted by the government before issuing the notification March 10.

The government notification issued on March 10 by Union Health Ministry Joint Secretary KL Sharma said various combination drugs, after examination by an expert committee, were found to be risking the lives of humans. The committee had submitted its recommendations to the central government on the prohibition of manufacture, sale and distribution of such drugs.

The drugs that have been banned in India are likely to be diverted to African countries or even SAARC countries except Pakistan and Afghanistan, as the Central government has not banned their exports.

A source in the drug control department said, “The products are not to be consumed in India, but if the importing country has no objections then the drug controllers cannot stop it.”

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Drug controllers say that they don’t have a say in what the manufacturers do with the recalled drugs. While the makers of cough syrups Corex and Phensedyl have approached the court and got a stay order, the others are still contemplating legal action. The problem is that this time the government has listed each combination and banned them instead of issuing a bulk order. This means that each pharma company will have to separately go to court for each combination. The Delhi High Court has scheduled a hearing for March 21.

Meanwhile, the government gazette gives minimum information about the reason for the ban. A senior pharma official on condition of anonymity said, “These combination drugs have gone through proper regulatory approvals. They have been in the market for a long time. Even the new combinations are approved and only then released in the market. How come they have become ineffective now?” The Central government has been asked to submit the details for ineffectiveness of Corex and Phensedyl to the court as the report is not in public domain.

A senior officer said, “There is very little information in public domain except that it is not viable for human consumption. The expert committee was set up in 2014 and the task was to classify the drugs into rational, irrational and those that needed further studies. Based on the responses and assessment of the products, the drugs have been banned.”

But a case to point is the combination of metformin+gliclazide+pioglitazone, which is used by diabetic patients and which was approved by the Drug Controller General of India. But the combination is now in the list of banned drugs. A senior doctor said, “This drug is very useful for diabetics. The government had approved it earlier, how can it be banned now? There are 80 combinations of pioglitazone which are effective for diabetic patients and their ban is going to affect the patients.”

The WHO had approved only 350 formulations of fixed dose combinations to treat prevalent diseases but the pharma companies got too ambitious and made more than 6,000 combinations.

Dr Hari Krishna, a senior physician said, “With 50 per cent of the market containing FDCs it had become a concern for prescribing medicines. For example if a person came with headache and high fever, the combination drugs prescribed mostly were medicines for headache, fever, body pain and cold. For the other two symptoms that did not exist (body pain and cold), the medicine was not required and it caused side-effects.”

Abbott India, along with another pharma company Macleods Pharma, moved the Delhi High Court Tuesday, against the government ban on combination drugs. The court meanwhile granted a stay on the ban on the drugs of the two companies.

The court, while granting a temporary stay on the ban, observed the interim relief to the pharma companies is justified. It also questioned the government on the sudden imposition of ban on combination drugs that have been in the market for the last 20 years, according to the daily.

U.S- based consumer healthcare company Procter & Gamble, whose product Vicks Action 500 Extra was banned, also approached the Delhi High Court for a stay on the ban.

Karnataka-based pharma companies like Embiotic Laboratories, Juggat Pharma and Anglo French have been granted interim relief by Karnataka High Court for the ban imposed by the

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Centre on sale of some of their fixed dose combination (FDC) drugs.

Another manufacturer Ce Chem has confirmed that it has also got a stay through the Indian Drug Manufacturers Association which filed a plea in the High Court for its members. Micro Labs too said it got a respite for the FDC ban from the Delhi High Court.

Pfizer Limited, whose popular cough syrup Corex was banned by the government, also managed to get a stay on the ban. The court hearing on the ban has been scheduled for March 21.

Market agency PharmaTrac said that Abbott and Pfizer may be the worst hit pharma companies due to the ban. Abbott may take a hit of Rs 485 crore and Pfizer Limited of Rs. 368 crore as a result of the government move, the Economic Times reported.

Impact of ban on consumers

Corex, Vicks Action 500, D Cold-Total, FLU Max, Phensedyl and a lot more OTCs (Over The Counter) drugs are now banned by the CDSCO. These are the drugs which are very commonly known to us mostly because of the brand name and their easy availability.

I interviewed five chemists in West Delhi to know the actual status of the banned drugs.

I was bit shocked about the information they gave me. First of all let me remind you once again that the Indian Gazette said that these drugs will not be manufactured and sold in India. But surprisingly these all drugs were available in those chemist shops.

They told me that the banned FDC drugs are available but will sell only if the doctor prescribes. This means that one can still buy these medicines by showing the prescription to chemist. So now one cannot just go and buy Vicks Action 500 without prescription.

Now this is strange because almost all of these banned FDC drugs come under schedule H. Now a Schedule H drug comes under the purview of Narcotic Drugs and Psychotropic Substances Act, 1985, it must carry the texts "NRx" and "Schedule H drug. Warning: To be sold by retail on the prescription of a Registered Medical Practitioner only." on the label prominently.

Now the question arises how were these drugs sold by the chemists without prescription for about 10-25 years before the ban? Not only this but now the chemist will give u these banned drugs with a bill.

Previously these drugs were easily available without any prescription and that too without bill. This is actually one of the reason for exponentially increase in the antibiotic resistance in us. People consume antibiotics even for cough and cold.

In a nut shell, Government says all the drugs are banned but they are available but can only be bought with a prescription of a registered medical practitioner with bill.

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7.0 Conclusion

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The Indian pharmaceutical sector is highly fragmented with more than 20,000 registered units. It has expanded drastically in the last two decades. The Pharmaceutical and Chemical industry in India is an extremely fragmented market with severe price competition and government price control. The Pharmaceutical industry in India meets around 70% of the country's demand for bulk drugs, drug intermediates, pharmaceutical formulations, chemicals, tablets, capsules, orals, and injectable. There are approximately 250 large units and about 8000 Small Scale Units, which form the core of the pharmaceutical industry in India (including 5 Central Public Sector Units).The Indian Pharmaceutical Industry, particularly, has been the front runner in a wide range of specialties involving complex drugs' manufacture, development, and technology. With the advantage of being a highly organized sector, the pharmaceutical companies in India are growing at the rate of $ 4.5 billion, registering further growth of 8 - 9 % annually.More than 20,000 registered units are fragmented across the country and reports say that 250 leading Indian pharmaceutical companies control 70% of the market share with stark price competition and government price regulations.

Today, when we read diabetes guidelines recommending early use of combination therapy, we tend to forget that Indian diabetologists have been using this form of treatment for over 40 years. Today, when the pharmaceutical industry celebrates the approval, by the FDA, of a FDC for diabetes, we do not realize that these combinations were the norm in India nearly half a century ago. The development and needs of FDCs plays a pivotal role in public health sector because of potential lower cost comparing to separate products. Simpler logistics and reduced development of resistance in case of antimicrobials. FDC therapy reduces poly pharmacy and pill burden, which improves patient compliance. Identifiable population group epidemiologically favours FDC. The rationality and therapeutic justification of all FDC’s are the most controversial issue in current clinical practice. The knowledge about FDC’s were lacking in resident doctors, which leads irrational prescription.

On March 10, 2016, the Central Drugs Standard Control Organisation, – or CDSCO, as it commonly known – issued a notification prohibiting the manufacture, sale and distribution of more than 300 FDCs drugs.

The ban on FDCs over safety and efficacy concerns will adversely affect MNCs like Abbott, Pfizer and domestic companies including Alkem, Ipca and MacLeods, according to market sources. Top brands which will face a ban include popular analgesics Zerodol and Sumo, dermatology drug Panderm Plus, anti-diabetic medicine Tripride, and gastro-intestinal drug Zenflox, besides cough syrups Phensedyl and Corex.

As per the notification gazette, a panel appointed by the government has found these medicines likely to involve risk to human beings and where safer alternatives are available. Besides this, these drugs are found to have “no therapeutic justification”, the notification gazette says.

There have long been safety and efficacy concerns over FDCs in general and action against them had long been awaited. However, the manner in which CDSCO acted underlined serious problems with the working of the drug regulatory system in India. These include the unclear division of functions between Central and State licensing authorities and inadequate guidelines for taking action against violations.

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These problems were exhaustively documented in a public interest petition filed against CDSCO by the Ranbaxy whistle blower, Dinesh Thakur, but dismissed by the Supreme Court only a day after the CDSCO notification.

But almost immediately, Pfizer dragged CDSCO to Delhi High Court, challenging the ban of one of the 338 FDCs, the popular cough syrup known as Corex.

The Delhi High Court granted an interim stay on the ban until March 21 to Pfizer, a similar injunction against the ban on Phensedyl (another cough syrup) and Vicks Action 500. The interim stay has been granted on the grounds that the drug has been marketed for 25 years and that the notification banning it does not disclose any “grave urgency”. The court’s order also records the alleged objection of the manufacturers that they had been denied a hearing before the ban was imposed.

There is no mention in the provision of the “grave urgency” that the Delhi High Court order mentioned while granting an interim stay on the ban. In any case, in previous instances involving Section 26-A bans, courts have been unsympathetic to the argument that the drugs in question have been available on the market for several years and therefore, there is no danger to public health.

This is because Section 26-A does not restrict the government’s power to life threatening situations. Bans may be imposed even when there is no therapeutic justification for the drug in question, even though the drug might not pose a risk to human health. In any case, courts have stayed away from reviewing the technical merits of bans, restricting their enquiry to whether the regulator had sufficient material on which to base its decision.

The contention of the manufacturers that they were entitled to a hearing before the ban was imposed has no basis in Section 26-A either. Courts have held that the Drugs and Cosmetics Act constitutes a complete code in itself and that principles of natural justice have no role to play in the exercise of a power that is primarily legislative in nature, like the power under Section 26-A.

What this means is that the manufacturers affected in this case might not be able to argue for the lifting of the ban solely on the ground that they were not offered the opportunity to make a representation. Even the fact that other manufacturers, unlike them, might have been given such an opportunity, is not sufficient to create an entitlement to a hearing.

Although there might be enough technical material and legal precedent to support CDSCO’s orders, it is very worrying that a situation such as this was allowed to arise, that is more than 300 drugs without any therapeutic justification were allowed to enter the market. Apart from concerns about safety and efficacy, many FDCs were also allowed to enter the market illegally. State Drug Authorities issued manufacturing licences for such FDCs without obtaining Central approval from CDSCO. This contravenes Rules 122B (3) and 122D, read with Rule 122E of the Drugs and Cosmetics Rules, 1945.

These provisions explicitly include FDCs within the definition of a “new drug”. When applying for approval to a State licensing authority to manufacture a new drug, the applicant must also provide evidence that the Central licensing authority, CDSCO, has approved the drug.

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These regulatory violations first came to the notice of CDSCO in early 2013, when it issued directions to State Drug Authorities to ask the manufacturers of such unapproved FDCs to demonstrate their safety and efficacy, failing which the drugs would be considered for prohibition. When very few manufacturers submitted such evidence to CDSCO, it directed them to make an application in Form 44 which would be considered in consultation with an expert committee.

Form 44 is used by applicants seeking permission to import or manufacture a new drug. Through its March 10-2016 notification, what CDSCO has done in effect is to refuse approval for the manufacture of new combinations, rather than prohibit the manufacture of drugs that were legally on the market. However, the use of Section 26-A to ban these drugs ignores this important legal distinction.

CDSCO and State Drug Authorities were caught sleeping on the job. The government must recognise that the weakness of the legal and regulatory framework contributed to this. One of the prayers in Dinesh Thakur’s petition asked for a reference to the Law Commission of India to consider the need for a new law on pharmaceutical regulation. Despite the dismissal of the petition by the Supreme Court, the government ought to initiate this process of its own accord.

“The pharmaceutical industry is so much frustrated and angered over the government decision. We are not against ban, but we stand against the way it was handled,” said D.G. Shah, secretary general, Indian Pharmaceutical Association (IPA). Codex, marketed by Pfizer, has been sold across the globe including highly regulated markets and there’s no justification for a ban in India, Shah said.

Companies like Abbott India, Macleods Pharmaceuticals, Pfizer India, Procter and Gamble Hygiene and Health Care (P&G), Glenmark Pharmaceuticals, RB India, Piramal Enterprises and Alembic Pharma got interim stay on the ban from the Delhi high court. The next hearing of the case is on 21 March.

Later, Wockhardt Ltd and Laborate Pharmaceuticals also won a stay order from the Delhi high court against the government ban

Included in the list of banned drugs are Abbott's Phensedyl and Pfizer's Corex. Both are widely used cough syrups made up of codeine and chlorpheniramine maleate.

These medicines along with 336 more are said to have no therapeutic justifications.

Pfizer India has already announced that it had stopped selling Corex, while Abbott is yet to give a statement about Phensedyl.

But the pharmaceutical industry too has a point. Out of the 6,220 samples that were taken up by the committee 963 have been found irrational after a year of study, but the government decided to ban only 338. If all the 963 drugs are banned the industry would have to take a hit of Rs 10,000 crore, which is nearly 10% of the pharmaceutical market. The industry has reason to feel betrayed given the opacity with which the entire process has been carried out. Though no one doubts the credibility of Professor Kokate or his group of scientists in the expert committee, the fact that the findings have not been made public is a

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valid reason for grievance. Banning a drug overnight would not only mean stopping production but also taking back the products that are in the supply chain pipeline. The 338 drugs that have been banned will result in a hit of around Rs 3,000 crore to the sector. But money is not an issue when it comes to public health and safety. If the poorest of poor patient can find money to pay for the medicine, the least the industry can do without griping is give him value for his money. The industry and the authorities who cleared the drugs need to be taken to task for allowing drugs that are banned abroad to be sold in India. Asking more time to clear up their inventories of products which should not be in the market in the first place does not make sense. Pharmaceutical companies willingly shell out millions of dollars to settle cases in the US for not following proper process let alone poor quality products. It is sheer hypocrisy when they cry foul for being pulled up in India for selling products which are no longer effective.

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8.0 Appendix

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References

1. http://pharmaceuticals.gov.in/pharma-industry-promotion - accessed on 06-04-162. https://www.linkedin.com/pulse/india-pharma-markets-morals-salil-kallianpur?trk=hp-feed-

article-title-comment – accessed on 06-04-163. http://qz.com/643748/what-a-ban-on-some-300-drugs-in-india-means-for-investors-and-

companies/ - accessed on 06-04-164. http://www.ibtimes.co.in/indian-pharma-sector-witness-rs-1000-crore-loss-due-drug-ban-

670895 - accessed on 07-04-165. http://www.ibtimes.co.in/pfizer-discontinues-manufacture-sale-corex-after-india-bans-over-

300-combination-drugs-670589 - accessed on 07-04-166. http://www.livemint.com/Money/HZJ4tIfRbWd8cyCfUouKtO/Pharma-stocks-dive-2055-this-

year-after-ban-on-combination.html - accessed on 07-04-167. http://www.financialexpress.com/article/industry/companies/over-300-drugs-banned-

complete-list-corex-vicks-action-500-extra/225735/ - accessed on 07-04-168. http://indiatoday.intoday.in/education/story/india-bans-drugs-including-household-

medicines/1/623442.html - accessed on 08-04-169. http://scroll.in/article/805348/corex-correction-the-real-problem-with-the-recent-ban-of-

344-drugs-in-india - accessed on 08-04-1610. https://garvsharma2050.wordpress.com/2015/12/01/awareness-about-banned-drugs-in-

india/ - accessed on 08-04-1611. BALASUBRAMANIAN J1, RADHIKA N2, BADARINATH AV2, “THE CRAVE OF FIXED DOSE

COMBINATION IN INDIAN MARKET”, Asian Journal of Pharmaceutical and Clinical Research, Volume 7, Issue 4, 2014

12. http://www.reuters.com/investigates/special-report/india-medicine-abbott/ - accessed on 10-04-16

13. http://apps.who.int/medicinedocs/en/d/Js4955e/7.html - accessed on 12-04-16 14. A BRIEF REPORT ON PHARMACEUTICAL INDUSTRY IN INDIA, July 2015, Corporate Catalyst

(India) Pvt Ltd, Sateesh Kulkarni.15. http://www.ibtimes.co.in/we-were-not-pre-informed-by-govt-abbott-india-drug-ban-

670872 - accessed on 14-04-1616. http://bdnews24.com/neighbours/2016/03/13/indian-ban-on-phensedyl-welcomed-in-

bangladesh - accessed on 14-04-1617. http://www.rediff.com/business/report/drugs-ban-these-are-the-worst-hit-brands-

companies/20160321.htm - accessed on 14-04-1618. http://timesofindia.indiatimes.com/business/india-business/Drug-ban-Pharma-market-to-

see-immediate-loss-of-Rs-1k-cr/articleshow/51418326.cms - accessed on 14-04-1619. http://www.business-standard.com/article/companies/banned-fdc-drugs-why-the-pharma-

industry-s-complaints-smack-of-hypocrisy-116032100098_1.html# - accessed on 14-04-1620. The Gazette of India, REGD. NO. D. L.-33004/99, EXTRAORDINARY, PART II—Section 3—Sub-

section (ii), PUBLISHED BY AUTHORITY, No. 608, NEW DELHI, THURSDAY, MARCH 10, 2016/ PHALGUNA 20, 1937

21. http://www.mapsofindia.com/my-india/government/344-fixed-drug-combinations-banned- by-health-ministry - accessed on 14-04-16

22. http://www.pharmabiz.com/NewsDetails.aspx?aid=94622&sid=1 - accessed on 15-04-1623. http://www.pharmabiz.com/NewsDetails.aspx?aid=94537&sid=1 - accessed on 15-04-16

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24. http://www.pharmabiz.com/NewsDetails.aspx?aid=94139&sid=1 - accessed on 15-04-1625. http://www.pharmabiz.com/NewsDetails.aspx?aid=94167&sid=1 - accessed on 15-04-1626. http://www.pharmabiz.com/NewsDetails.aspx?aid=94244&sid=1 - accessed on 15-04-1627. http://www.medindia.net/patients/patientinfo/drugs-banned-in-india-as-of-march-

2016.htm - accessed on 15-04-1628. http://profit.ndtv.com/news/industries/article-drug-ban-delhi-high-court-to-hear-plea-of-

pharma-companies-1289297 - accessed on 15-04-16

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