indian Journal of Medical Ethics Vol X No 2 April-June 2013
`
`artiCles
`
`The crisis in access to essential medicines in india: key issues which call for
`action
`
`ANUrAG BhArGAVA1, SP KALANTrI2
`
`1Department of Medicine, himalayan Institute of Medical Sciences, Jolly Grant, Dehradun, Uttarakhand 248 140 INDIA 2Department of Medicine, Mahatma Gandhi
`Institute of Medical Sciences, Sevagram, Maharashtra 442 102 INDIA Corresponding author; Anurag Bhargava e-mail: anuragb17@gmail.com
`
`Abstract
`The government is planning to introduce free generic and essential
`medicines in public health facilities. Most people in India buy
`healthcare from the private sector, a compulsion that accounts
`for a high proportion of healthcare-related expenditure. To reduce
`the burden of healthcare costs, the government must improve
`availability and affordability of generic and essential medicines
`in the market. It can do so because India’s large pharmaceutical
`industry is a major source of generic medicines worldwide.
`
`In this article, we discuss three factors that have impeded access
`to generic and essential medicines: (1) mistaken notions among
`policymakers, prescribers and patients about branded drugs and
`generic drugs in India; (2) high prices of medicines due to the
`progressive dismantling of the system of regulation of medicine
`prices, and (3) a drug approval and regulatory system that allows
`medicines (including fixed dose combinations) of doubtful efficacy,
`rationale, safety and public health relevance to dominate the
`market at the cost of access to affordable generic and essential
`medicines. The consequences of ill-health and wasted expenditure
`on drugs raise issues of public health ethics.
`
`Improving access to essential medicines in India is an urgent
`public health and ethical imperative. This should include improved
`public provisioning, a system of regulation of drug prices, and an
`evidence-based drug approval process.
`
`Introduction
`in india, a silent crisis in access to essential medicines confronts
`most patients who seek treatment of acute and chronic
`diseases. close to 40% of indians live on less than US $1 per
`day and most of them pay out of pocket for using healthcare.
`Out-of-pocket spending in india is over four times higher than
`public spending on healthcare. Unexpected illness can have a
`catastrophic effect on the family of the ill person: direct out-of-
`pocket payments could push 2.2%% of all healthcare users and
`one-fourth of all hospitalised patients, into poverty in a year
`(1,2).
`
`in addition, most indians pay for medicines – a key factor that
`can contribute to the impoverishing effect of out-of-pocket
`payments for healthcare. According to the World Health
`Organization (WHO), an estimated 649 million people in india
`do not have regular access to essential medicines (3). Public
`provision of these medicines is poor; the median availability
`
`[ 86 ]
`
`of 30 essential medicines in six states in india varied between
`0% and 30 % (4). Patients are forced to buy medicines from
`the private market, a compulsion that often spells calamity
`for those who can ill afford the twin burdens of sickness and
`healthcare costs.
`
`For example, india has the largest number of patients with
`diabetes in the world. A study has shown that patients
`belonging to the low income group in urban india were
`spending 27% of their annual income and those in rural
`india 34% of their annual income on diabetes care; most of
`this was spent on purchase of medicines (5). A recent study
`calculated the expenditure incurred on outpatient treatment of
`community-acquired pneumonia as a proportion of the mean
`per capita expenditure on food (6). Urban patients spent 17.6
`% of their mean per capita expenditure on food (rural patients
`spent 23.4%) on the medicines prescribed for community-
`acquired pneumonia (6). Studies have also shown that of the
`rising out-of-pocket expenditures on healthcare, which push
`an estimated 32-39 million people below the poverty line
`annually(1,7), more than 70% of expenditure was incurred on
`purchase of medicines (1,7,8).
`
`The reality of healthcare in india is that the private sector now
`caters to 80% of outpatient and 60% of inpatient care (9).
`Patients are therefore forced to purchase medicines from the
`market, which functions (and is being allowed to function) in
`a manner antithetical to india’s public health needs. Not only
`do public health systems fail to provide essential drugs to
`patients, but the indian pharmaceutical market is flooded with
`overpriced medicines that are inappropriate and irrelevant to
`the public health needs of the country.
`
`The lack of access to essential medicines -- 348 drugs are listed
`in the national list of essential medicines of india (10) -- is the
`result of the inadequate budgetary provision for healthcare,
`the lack of a comprehensive policy on medicines in india, and
`a weak regulatory framework which allows medicines to be
`produced, promoted and prescribed without assurance of
`their rationality, quality or reasonableness of price. To reduce
`healthcare costs, it is important that people are able to access
`medicines of assured quality that are efficacious, safe and
`affordable. These essential medicines must satisfy the priority
`healthcare needs of a majority of the population and must be
`available as part of a basic healthcare system (11).
`Exhibit 1120
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`Government announcement on free generic and
`essential medicines
`Some activities in 2012 suggest that this scenario might
`change. in February 2012, partly as a response to the persistent
`demands of civil society and the recommendations of the
`High Level Expert Group of the Planning commission, the
`government announced plans to increase the outlay for health
`to 2.1% of the gross domestic product by the end of the 12th
`Five year Plan (2012-17). The President’s speech in the budget
`session of 2012 referred to plans by the government to ensure
`“universal access to free generic essential medicines in public
`health institutions in a time-bound and phased manner” (12).
`This plan was also referred to by the Prime Minister in his
`2012 independence Day address (13). This was a welcome
`announcement (even if long overdue) articulated at the highest
`level of the government, although a year later the scheme has
`still not received adequate budgetary allocation to allow for
`its launch. if translated into reality by exercise of political will,
`good governance and allocation of adequate resources, it can
`revitalise the public health system in india.
`
`in this article, we discuss three factors that have impeded
`access to affordable generic and essential medicines in india:
`(1) mistaken notions among policymakers, prescribers and
`patients about branded drugs and generic drugs, (2) high
`prices of medicines due to progressive dismantling of the
`system of regulation of medicine prices, and (3) a drug approval
`and regulatory system that allows medicines (and fixed dose
`combinations) of doubtful efficacy, rationale, safety and public
`health relevance to dominate the market at the cost of access
`to affordable generic and essential medicines.
`
`1. Mistaken notions of ‘branded’ and ‘generic’ medicines in
`India
`
`in india, confusion and misinformation about generic medicines
`abound. The confusion is spread across stakeholders including
`the public, prescribers, policymakers and pharmaceutical
`trading agencies.
`
`in their 2012 addresses to the nation, the President and
`the Prime Minister emphasised the importance of access
`to generic medicines, and rightly so, because worldwide,
`generic medicines are being seen as an answer to soaring
`healthcare costs. For example, in the US, not only are six of
`every 10 prescriptions filled with generic medicines (14), but
`pharmacists are also allowed to replace branded medicines
`with generic ones. by contrast, in india, home of one-fifth of
`the world’s production of generic medicines, a consumer finds
`it difficult to access low-cost generics. We explain this paradox
`by clearing the misinformation about branded and generic
`medicines in india.
`
`is
`is defined as a “drug product that
`A generic drug
`comparable to brand/reference listed product in dosage form,
`strength, route of administration, quality and performance
`characteristics, and intended use” (15). in countries where
`product patent laws are in effect, the originator firm holding
`the patent markets the medicines under a trademarked name
`
`indian Journal of Medical Ethics Vol X No 2 April-June 2013
`
`with no competition for a period of up to 20 years. in these
`countries, generic medicines are low-cost versions of the
`innovator product, produced by a number of manufacturers
`after the patent on the medicine expires. Thus generic
`medicines are off-patent medicines made by companies other
`than the originator company, and may be marketed under a
`trade name (branded generic) or under the international non-
`proprietary name, or iNN (unbranded generic). For example,
`Paracetamol is marketed as crocin, calpol, or Metacin (branded
`generic), or simply as Paracetamol (unbranded generic).
`Generic versions of the original patented drug, chemically
`identical to the originator product, are required by law to
`satisfy the same standards of quality, and are similar in safety,
`efficacy, risks, benefits, and intended use. Sceptics often raise
`the issue of bioequivalence and therapeutic equivalence of
`generic and brand/reference products. Actually, drug products
`are considered bioequivalent if there is no clinically significant
`difference in their bioavailability (as measured by extent and
`rate of absorption, and maximum blood concentration) (16).
`Generic drugs are identical and bioequivalent to an innovator
`brand (17). in the case of oral drugs, if the blood concentrations
`of two drugs are the same, then their concentration at the site
`of action and their effectiveness are also considered to be the
`same (16). There are few cases in which two drug products with
`the same active ingredient in the same dose may have different
`bioavailability (18). in all other circumstances, generic and
`brand name drugs can be considered interchangeable (19). A
`systematic review of 38 randomised controlled trials of generic
`and brand named cardiovascular drugs concluded that they
`were clinically equivalent (20).
`
`The term “generics” is understood differently in india. in india,
`there was no patent protection for medicinal products before
`2005 (only processes for manufacture of medicinal products
`could be patented); and the term “generic medicines” was
`used for those medicines which were marketed under the
`generic name (iNN). A recent term for generic medicines used
`by the WHO is “multi-source pharmaceutical products”, which
`avoids the prevailing confusion between generic medicines
`(which can be marketed under a brand name), and the generic
`(non-proprietary) name of a medicine (21). in countries like
`the USA, prescriptions for unbranded generics predominate,
`while branded generics are a small part of the market -- 58%
`of the dispensed prescriptions were for unbranded generics
`compared to only nine per cent for branded generics (14).
`
`We use the term “generic” in line with its global usage to
`denote medicines which are off patent. The term used in this
`sense would represent virtually all the drugs in the indian
`pharmaceutical market, since few enjoy patent protection. in
`india, the basic division is therefore not between medicines
`under patent and off-patent medicines, but between
`unbranded medicines (generic
`in the
`indian sense) and
`branded medicines. branded drugs
`in
`india are actually
`“branded generics” which are often misunderstood by patients,
`or even the media, as “patented” medicines (22), which they
`are not.
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`indian Journal of Medical Ethics Vol X No 2 April-June 2013
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`The brand scam
`
`Drug makers and pharmaceutical trading agencies create
`an impression that branded generics are vastly superior to
`unbranded generics (which are often procured in the public
`health system and are available to patients free of cost). Even
`medical professionals consider unbranded generics to be
`substandard medicines. To add to the confusion, branded
`generics in india have been artificially divided by academicians
`and policymakers into two categories: “branded” products,
`which apparently refer to drugs made by “reputed” companies
`and promoted through doctors, and so-called “branded
`generics”, drugs apparently made by less reputed companies
`and promoted through retailers (23). Patients value quality,
`safety and cost-effectiveness of a medicine; it matters little to
`them whether the medicine is branded or unbranded and
`whether it is promoted through the retailer or the doctor. All
`drugs in india also have to meet the same requirements with
`regard to quality, irrespective of whether they are marketed
`under the iNN or trade name, and regardless of the route
`of promotion.
`
`Drug makers and pharmaceutical trading agencies aggressively
`promote their brand name drugs, often using dubious means
`(24). Each brand claims superiority over competing brands or
`unbranded medicines. The top 50 companies spent Rs 5,840
`crore on drug promotion in a single year (25). This practice and
`cleverly created myths have made it difficult for patients to
`access low cost medicines in india. The argument that brand A
`is better than brand B does not hold for a number of reasons.
`
`First, drug makers often market the same molecule under
`a variety of brand names and at widely differing prices.
`For example, Ranbaxy uses two brand names to market
`ciprofloxacin: cifran (the best-selling brand) and ciproace
`(the lesser-known brand). A tablet of cifran (500 mg) costs Rs
`9.90; that of ciproace Rs 6.20 (26). Does it mean that cifran kills
`bacteria faster than ciproace does? How would Ranbaxy justify
`the difference in the prices of its two brand names?
`
`Second, drug makers also market both so-called brands and
`branded generics. A recent study did not find any difference
`in quality between brands and so-called branded generics
`made by the same company (23), yet the difference in price is
`substantial.
`
`Third, medical professionals often indicate that they trust drugs
`made by highly reputed companies. Their trust is misplaced
`because reputed companies in india often do not manufacture
`but only market medicines (which may range from vitamins
`to very expensive antibiotics). The medicines marketed by
`reputed companies are actually manufactured by so-called “less
`reputed” companies. For example, Glaxo Smith kline (GSk) is
`well known for its brands such as Zevit (multivitamin with zinc),
`Augmentin (amoxicillin-clavulanate: an oral and parenteral
`antibiotic), and Esblanem (Meropenem: an antibiotic costing
`Rs 1,200 per gram). Little do the doctors and public know that
`GSk gets them manufactured by less well-known companies
`such as Remidex, Medreich and Hospira and merely markets
`these brands (information from product packages). This is true
`for hundreds of other companies as well.
`
`Fourth, the companies argue that drugs promoted through
`chemists are cheaper than those promoted through doctors,
`because they do not have to offer the incentives and freebies
`that they routinely offer to doctors. This argument also does
`not hold because companies promote medicines to doctors
`as well as chemists (27).While doctors are offered gifts and
`even incentives (28), chemists are also offered bonuses on
`brands and hugely discounted prices on commonly used
`drugs (29,30). Recent studies have shown that trade margins
`in india for branded drugs can vary from 200% to over 1,000%
`(23, 30). Self-medication practices are widespread across the
`different socio-economic groups in india, as is the practice
`of over-the-counter drug dispensing. For minor ailments,
`consumers often do not see a doctor and prefer to medicate
`themselves. blissfully unaware of the profit margins on simple
`antibiotics, cough syrups, painkillers or anti-histaminics, they
`end up paying exorbitant prices for the over-the-counter drugs
`they buy from local chemists (31). Abroad, generics are much
`cheaper than the originator product (32). Not so in india. The
`so-called branded generics have a printed maximum retail
`price which is sometimes even higher than that of so-called
`branded product (23).
`
`Prescription malpractice
`
`We wish to emphasise that the indian pharmaceutical market
`is entirely a generics market, one in which a few branded
`generics, masquerading as innovator products, monopolise
`the market. There are thousands of brand name drugs in this
`market and patients have little access to low-cost branded or
`unbranded medicines. For patients to access low-cost generic
`drugs, it is important that drug companies reduce their profit
`margin, pharmacies stock and promote them and prescribers
`start writing them. Although the Medical council of india’s code
`of ethics for doctors explicitly mentions that “Every physician
`should, as far as possible, prescribe drugs with generic names...”
`(33), this practice is seldom followed.
`
`We believe that doctors must write drugs by generic names
`in both public and private sectors. To begin with, public
`health facilities must enforce this practice because unbranded
`medicines are procured and dispensed in these institutions.
`The usual practice of patients seeking healthcare in the public
`health facilities being forced to buy brand name medicines
`from private chemists must be checked (22). The generic-name
`prescriptions in the private sector haven’t succeeded because
`private pharmacies either do not stock them or the pharmacists
`replace low-cost drugs with expensive branded ones. Therefore
`the government’s advice to all doctors to prescribe by generic
`name cannot be translated into practice. Also, when doctors
`prescribe fixed dose combinations (FDcs), they always choose
`brand name drugs. They argue that because FDcs have
`multiple ingredients, they find it difficult to prescribe them by
`their non-proprietary names. Prescribing by generic name in
`india will take root only when doctors prescribe unbranded
`single ingredient medicines, and take irrational FDcs off their
`prescriptions.
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`indian Journal of Medical Ethics Vol X No 2 April-June 2013
`
`Regulatory negligence
`
`Market failure
`
`The drug regulatory agencies in developed countries like the
`US, canada, the Uk and Australia promote the use of generics
`and highlight their therapeutic equivalence to brand name
`originator products. in india, most prescribers do not know
`there is no difference, in pharmaceutical terms, between
`unbranded and branded medicines, or between brands, and
`the drug regulatory authorities make no effort to educate
`them. both doctors and patients prefer brand name drugs over
`generic drugs because the latter, in their eyes, are low quality
`and substandard -- if not counterfeit -- drugs. Patients prefer
`to spend on brands they can trust, and consider a company’s
`visibility and corporate image as a proxy for authenticity and
`quality control.
`
`if the government were to provide quality assurance of all
`medicines available in the market, then a truly competitive
`market for generics competing on the basis of price could
`emerge in india which would immensely benefit the consumer.
`There would be increased prescriber support for unbranded
`generics in india and a better performance of schemes like
`the Jan Aushadhi stores which aim at providing good quality
`low-priced, unbranded medicines from five public sector
`companies (34, 35). Our own experience of running pharmacies
`at secondary and tertiary care institutions, based on low cost,
`unbranded as well as branded, generics sourced from carefully
`chosen drug companies, has been very positive in terms of
`savings in cost to patient and patient outcomes.
`
`brand name medicines in india cause the cost of treatment
`to spiral and are also a frequent but under-reported cause of
`medication errors. More than 60,000 brands exist in the indian
`market but there is no registry of these drugs. As a result, brand
`names of medicines with dissimilar therapeutic effects (look-
`alike or sound-alike drugs; Table 1), result in serious medication
`errors (36). in our clinical practice, almost every day we see
`dozens of patients who are unable to find the drugs their
`doctors have prescribed, because the brand name drugs in the
`prescription they carry are available at only a few select shops
`close to their doctor’s clinic.
`
`2. overpricing of medicines in India: the imperative for
`price regulation
`
`india’s
`regulation has been a key element of
`Price
`pharmaceutical policy since 1970. Prices of medicines have
`however been rising over the past few decades due to
`progressive dismantling of the system of price regulation. The
`Drug Prices control Order (DPcO) initially placed price limits
`on 348 medicines deemed essential in india, a number that
`shrank to just 74 drugs by 1995 (37). Most drugs required to
`treat diseases of public health importance were either under-
`represented in this list or were not represented at all (38). The
`list did not include vaccines, oral rehydration salts, drugs for
`cancer or coronary artery disease, and included very few drugs
`for respiratory diseases, hypertension, and diabetes (38).
`
`The government tried to justify its lax control over regulation
`of drug prices by arguing that competition alone was enough
`to control their prices, an expectation belied by subsequent
`developments. Drugs not listed in the DPcO started getting
`costlier, and the rise in drug prices consistently outstripped the
`prices of all other commodities (37). For 17 years -- 1995 to 2012
`-- the number of drugs under price control did not change.
`
`A public interest litigation filed in the Supreme court of india is
`seeking to re-introduce price regulation of all the medicines in
`the National List of Essential Medicines (NLEM). At the behest
`of the court, the NLEM was recently revised (10) and a revised
`National Pharmaceuticals Pricing Policy is on the anvil (39).
`
`The government, however, intends to switch to a market-
`based pricing formula which, if implemented, will either only
`marginally reduce drug prices, or may actually increase them
`(40,41). Several publications have pointed out that the new
`policy may adversely impact public health in india (42-44).
`An analysis of the top-selling 300 brands suggested that 62%
`of them contained medicines outside the NLEM, and of the
`115 FDcs only 20% could be considered rational (45). These
`medicines and such combinations would be outside the
`purview of price control, and this would reduce the efficacy of
`price control as an intervention to reduce healthcare-related
`costs.
`
`Are price differentials ethical?
`
`Medicines are overpriced in india. in india, the pharmaceutical
`sector shows three types of price differentials which reflect
`this overpricing. The first differential is the greater than
`10-fold difference in the maximum retail price of different
`brands of the same medicine which is seen in the market
`(Table 2). Differences between retail prices of perhaps a lesser
`magnitude are seen across therapeutic categories of medicines
`in india. The disconcerting fact is that in india the market leader
`in a particular therapeutic segment is also the price leader,
`or amongst the highest priced medicines in that segment.
`For example, Atorva, an anti-lipid brand name drug, outsells
`hundreds of brands, some of which are 10 times cheaper
`(Table 2). This is clearly an indication that market forces
`fail to regulate drug prices, as was naively assumed by the
`government over the years. This state of affairs exists because
`patients pay but do not decide, while doctors – the key players
`who are often heavily influenced by the pharmaceutical
`companies – decide but do not pay. in such a situation,
`patients with diseases like diabetes, hypertension or cancer
`pay substantially more if their doctor prescribes the more
`expensive brand for each of these conditions.
`
`is between
`in prices
`inexplicable difference
`The second
`the price to retailer and the price to consumer for branded
`generics. A study found trader margins for the branded
`generics promoted through retailers of the order of 201-
`1,016% (23). These enormous trade margins have been known
`to the government since 1998 as pointed out by the Drug Price
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`indian Journal of Medical Ethics Vol X No 2 April-June 2013
`
`control Review committee. This vast differential points to the
`enormous mark-ups which exist in drugs and which are being
`pocketed either by the pharmaceutical trader or the company
`(hospitals and doctors who dispense the drugs also share the
`profits). if drug makers agree to reduce the exorbitant profit
`margins, and drug prices are tightly regulated, all drugs might
`become available at affordable prices.
`
`The final revealing differential is between the price paid
`for purchase of medicines in pooled public procurement
`programmes in Tamil Nadu and other states which buy quality
`assured medicines, and of the brands which sell in the market.
`For example, Tamil Nadu procured 10 tablets of Omeprazole
`(a commonly used drug for acid peptic disease) for Rs 2.4
`while the market leader sells at Rs 39.7 for 10 tablets (46).
`Similarly, Tamil Nadu procured human insulin at nearly a third
`of the prevailing market price. The variation in retail prices,
`the margins offered to the traders, hospitals and doctors
`who dispense the drugs and the difference between retail
`prices and prices in pooled procurement are unique to the
`pharmaceutical sector.
`
`These differentials raise an ethical question for public policy.
`These price variations may not be illegal, but are they morally
`right? Are these wide variations in drug prices – which have no
`parallel amongst all other commodities – ethically acceptable
`when access to medicines can constitute the difference
`between life and death? Should the government not intervene
`to ensure that patients are not at the mercy of the prescribers’
`whims and the vagaries of the market? Should the ambit of
`price regulation not cover all medicines as suggested by the
`National commission of Macroeconomics and Health (37),
`rather than just the 348 medicines mentioned in the NLEM?
`Won’t this control of prices, limited to those of essential
`medicines, induce the industry to migrate from production
`of price-controlled medicines to those outside control? This
`selective approach to price control could ultimately promote
`the production and marketing of medicines which are not in
`the NLEM.
`
`3. The need for evidence-based drug approval and
`improved access to essential medicines
`
`industry have acquitted
`its pharmaceutical
`india and
`themselves very creditably on the global platform. indian
`generics account for about 40% of the anti-retroviral medicines
`provided globally. Worldwide, these
`low-cost high-quality
`medicines are a lifeline to millions of people. There are an
`estimated 10,563 manufacturers in india, and more than 65,000
`formulations (47).
`
`These numbers look impressive but the paradox is that, at
`home, “large portions of the population lack access to even
`the most essential drugs. The limited funds available are
`frequently spent on ineffective, unnecessary, or dangerous
`medications.”(48:16.2). The money spent on overpriced
`medicines is very often also a waste of precious resources.
`This is because the indian pharmaceutical market is full of
`ineffective, unnecessary medicines. Since these medicines
`
`outnumber those which are cost-effective, they directly impact
`the availability of and access to essential medicines (49).
`
`Lack of essential medicines in the market
`
`iron deficiency anaemia is an important public health problem
`in india, associated with low birth weight in infants, pregnancy-
`related deaths, and decreased work capacity. Ferrous sulphate
`and ferrous fumarate – low cost medicines recommended
`for treatment of iron deficiency which are distributed free
`of cost in public health facilities – are not available in most
`drug stores in india. The July 2012 edition of Current Index of
`Medical Specialities (CIMS), a prescriber handbook, does not
`mention a single preparation which contains ferrous sulphate
`in the dose mentioned in the NLEM 2011(46). Hundreds of
`iron preparations are available in the market- they contain
`salts with poor efficacy or co-existing with other nutrients
`(vitamins, minerals including zinc, amino acids) which do
`not increase their efficacy (50). yet they cost much more than
`simple iron preparations and push up the cost of treatment
`of iron deficiency anaemia as much as 70-fold, according
`to an estimate (51). We are unable to understand why such
`ineffective and irrational preparations continue to be in the
`market and why iron pills are not under price control.
`
`Dexorange was a market leader for the treatment of iron
`deficiency anaemia. Although this drug contained a poorly
`absorbed salt of iron and haemoglobin that came from
`slaughterhouse blood, (52) it enjoyed a lot of support from
`medical professionals between 1970 and 2000 (when the use of
`haemoglobin in anaemia preparations was finally banned). This
`combination had no parallel anywhere in the world. Similarly,
`the market is flooded with irrational fixed dose combinations to
`treat infectious diseases, as well as “me-too” drugs -- members
`of the same group as essential medicines which do not confer
`any therapeutic advantage but are more expensive. it is a
`moot point whether the 11 calcium channel blockers available
`in the indian market fulfil any therapeutic need (46). On the
`other hand, essential medicines are scarce. Thiazide diuretics
`are amongst the cornerstones of treatment of hypertension.
`However, there were only five brands of thiazides listed in CIMS,
`while there are 131 brands of thiazides in combination with
`other medicines (26).
`
`Unnecessary and irrational fixed dose combinations
`
`(FDcs) are combinations of
`Fixed dose combinations
`drugs, used
`in situations where such a combination
`is
`pharmacologically justified. More than 40% of the formulations
`in india are composed of FDcs (53), a proportion which
`is unprecedented. For example the NLEM which lists 348
`medicines has only 15 combinations of medicines (10). in
`contrast, in the market there are more than 15 combinations of
`paracetamol alone.
`
`FDcs are justified when the combination of the active drugs
`increases efficacy, decreases adverse effects, reduces the risk of
`drug resistance, lowers prescription cost, simplifies therapy or
`promotes adherence to therapy (21). Such combinations with a
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`therapeutic advantage are therefore justified (some examples
`are oral contraceptives, anti-malaria therapy, anti-Tb drugs, HiV
`therapy, and drugs for asthma, hypertension and diabetes). A
`basic requirement is that the drugs comprising the FDc should
`have compatible pharmacokinetics and pharmacodynamics.
`The major disadvantage of FDcs is an inability to vary the
`dose of the individual components of the combination, and
`increased incidence of adverse effects (21).
`
`in india, the FDcs often lack pharmacological justification.
`india’s most widely available antibiotic combination of
`ampicillin/amoxicillin and cloxacillin
`is pharmacologically
`irrational (54), compromises the treatment of staphylococcal
`infections because the dose of cloxacillin in the FDc is half of
`what it ought to be, and promotes the development of drug
`resistance. The use of other FDcs of antibiotics like ciprofloxacin
`+ metronidazole has contributed to increasing resistance in
`enteric infections like typhoid fever
`
`FDcs often also contain chemicals which lack efficacy but
`increase the cost of therapy. For example, an FDc of painkillers
`with serratiopeptidase, a drug isolated from silkworm intestine,
`is commonly prescribed in india. This drug was voluntarily
`withdrawn from the market in Japan by its manufacturer
`Takeda in 2011, when clinical trials failed to show evidence of
`its efficacy compared to placebo, but continues to be popular
`in india (55).
`
`A number of FDcs are downright hazardous. The European
`Medicines Evaluation Agency approved Nimesulide only for
`restricted and short term use in adults. The agency warned that
`combination of this drug with other painkillers like paracetamol
`c