Irrational Combinations and Banned Drugs

Pharmabizz.comWednesday, August 06, 2003 08:00 IST Dr R N Gupta

More than 60,000 branded formulations are available in India. These preparations contain either single drug or drugs in fixed dose combination (FDC). All formulations are used for treatment or prevention of diseases. Out of it only few drugs are lifesaving and essential drugs, otherwise maximum of them are available as alternative or substitute to each other.

At the same time it is clinically proved that almost all the drugs have side effect at therapeutic level besides toxic effect. The unwanted side effect is referred to as adverse drug reaction (ADR). Hence a drug is used or prescribed by physician on seeing risk-benefit ratio. 

Though the drug is approved by the Drugs Controller General India for manufacturing and marketing in country only after consideration of all aspects such as therapeutic effect, side effect, toxic effect etc; the physician has to follow rational prescription practice in consideration of drugs available in the market. 

The DCGI has allowed so many drugs having serious ADR after considering their therapeutic justification but those drugs are allowed with an indication to be printed on label of product i.e. Erythromycin, Chloramphenicol, Metronidazole, Iodo-chlorohydroxy quinoline etc.

It is a fact that on seeing serious hazardous effect of drug Thalidomide in 1960 in UK, the FDA of all the countries gave a thought on banning of drugs. Accordingly in our country, after amendment of Drugs Act in 1982, Government has acquired the power to prohibit the manufacture and sale of drugs and fixed dose combinations or irrational drugs. The government, subsequently, issued a first gazette notification in July 1983 banning several drugs and their FDC after due consideration. A ban or restricted use order is being issued on a continuous basis on seeing ADR on Indian patients. This is being done in the interest of common people of India and also to safeguard

their health from menace of ADR of drugs. 

Till date the Indian government has banned several FDCs and imposed restriction on many drugs and their combinations with other drugs for its manufacturing and marketing in India. Following is the list:

1. Amidopyrine2. Phenacetin3. Sulphanilamide4. Practolol5. Methapyrilence and its salts6. Penicillin skin/ eye ointment7. Tetracycline liquid8. Oxytetracycline liquid oral preparation9. Demeclocycline liquid oral preparation10. Methaqualone11. FDC of chloramiphericol with other drugs for internal use12. FDC of Ergot with any drugs13. FDC of Vitamins with anti-inflammatory agents and tranquilisers14. FDC of Atropine with analgesics and antipyretics15. FDC of Yohimbine and strychnine with Testosterone and vitamins.16. FDC of iron with Strychnine, Arsenic and Yohimbine.17. Chloral hydrate18. FDC of sodium bromide with other drugs.19. FDC of Tetracycline with vitamin C.20. FDC of antihistamins with antidiarrhoeals.21. FDC of Penicillins with Sulfonamides22. FDC of vitamins with analgesics23. FDC of prophylactic vitamins with Anti TB drugs except isoniazid with Pyridoxine Hydrochloride (Vitamin B6).24. FDC of Strychnine and Caffeine in Tonic.25. FDC of Hydroxy Quinolines groups of drugs with other drugs and liquid oral antidiarroheal or any other dosage form for paediatric use except for external use.26. FDC of corticosteroid for internal use27. FDC of Anabolic steroid with other drugs.

28. Combination of high dose of Estrogen and Progesterone (low dose combination is allowed for its use as contraceptive)29. FDC of Sedatives/ hypnotics/ anxiolytics with analegesic and antipyretics.30. FDC of anti-TB drugs except the under-stated combinations.I II(a) (I) Pyrizinamide 1000mg; 1500mg(II) Rifampicin 450mg; 600mg(III) Isoniazid 300mg; 300mg(b) (I) Ethambutol 600mg; 800mg(II) Isoniazid 200mg; 300mg.

31. FDC of Histamin H2 receptor antagonists with antacid except any combination approved by DCGI.32. Patent and proprietary medicines having alcohol more than 20% except preparation listed in IP.33. All preparations containing chloroform exceeding 0.5% w/w or v/v whichever is appropriate.34. FDC of anthelmintics with cathartics or purgatives except for piperazine.35. FDC containing more than one antihistaminic drug.36. FDC of Salbutamol or any other bronchodilator with central acting antitussives and/ or antihistamines.37. FDC of Laxatives and/ or antispasmodic drugs in enzyme preparations.38. FDC if metoclopramide with other drugs except with Aspirin/ Paracetamol.39. FDC of centrally acting antitussives with antihistamin as having atropine like activity in expectorent.40. Preparations claiming to combat cough associated with asthma that contain a centrally acting antitusive and/ or antihistamine.41. Liquid oral tonic having glycerol phosphates and other phosphates and/ or CNS stimulants and such preparations having alcohol more than 20%.42. FDC containing Pectin and/ or Kaolin with any drug which is systemically absorbed through GI tract.43. Toothpaste/ toothpowder containing tobacco.44. Dovers powder IP Dovers Powder IP Tablets.45. Antidiarrohoeal preparations containing kaolin/ pectin/ attapulgite/ activated charcoal.46. Antidiarrohoeal preparations having phthalye sulphathiozole,

Sulphaguinidine, succinic sulphathiozole, Neomycin, streptromycin, dihydro streptomycin or their salt.47. Antidiarrhoeal formulation in any form for Pediatric use containing Diphenoxylate or Loperamide or Atropine or belladonna including their salts, esters or metabolites or their extracts or alkaloids.48. FDC of antidiarrhoeals with electrolytes, 49. Oral Rehydration salts (ORS)-other than conforming to WHO formula or Pharmacapoeial preparation.50. FDC of Analgin with any other drugs.51. FDC of Dextropropoxyphene with any other drug except with antispasmodics and or NSAID52. FDC of Phenylbutazone or Oxyphenbutazone with other drugs.53. FDC of allopathic drugs with Ayurvedic, Siddha or Unani drugs.54. Mepacrine Hydrochloride (Quina-crine and its salts) in any dosage form for use for female sterilization or contraception.55. Fenfluramine and Dexfenfluramine.56. FDC of streptomycin with penicillin.57. FDC of Vitamin B1, B6 & B12.58. Fixed dose combination of Nitrofuratoin and Trimethoprim.59. Fixed dose combination of Phenobarbitone with any antiasthamatic drugs.60. Fixed dose combination of Phenobarbitone with Hyoscin and/orHyoscyamine. 61. Fixed dose combination of Phenobarbitone with Ergotamine and/orBelladona.62. Fixed dose combination of Haloperidol with any anti-cholinergic agent including Propentheline Bromide.63. Fixed dose combination of Nalidixic acid with any antiramoebics including Metronidazole.64. Fixed dose combination of Loperamide Hydrochloride with Furazolidone. 65. Fixed dose combination of Cyproheptadine with Lysine or Peptone.66. Fixed dose combination of Diazepam and Diphenhydramine Hydrochloride.67. Cisapride- Only qualified gastro-enterologists such as super specilists holding DM in gastro-enterology are permitted to prescribe cisapride.68. Astemizole 69. Terfenadine

70. Sildenafil citrate. To be prescribed by endocrinologists, Urologists and Psychiatrist only.

The safety of health of a patient from drug is a vital aspect during treatment. The health professionals -- physicians, pharmacists and nurses have to prescribe, handle and administer the medicines respectively. So it is imperative for them to acquaint themselves with the above list. In addition to it, they should also go through the notification issued time to time by DCGI. This helps them to use proper medicines only and also to save patients from unsafe drug. Further it is also imperative for the industrial pharmacists and marketing professionals to keep themselves abreast with list of banned drugs, drugs of restricted use and banned FDCs. This ultimately helps them in formulating right products mix and a proper marketing strategy. Lastly it saves the Indian patients from hazardous drugs.

Rationality of Fixed Dose Combinations: Necessity to Weed out the Irrational Combinations Mushrooming in Pharmaceutical IndustryBy - 01/20/2008

An innovation in drug therapy can take various forms, including new agents, new indications for existing drugs, and new dosage forms with improved pharmacological profiles.

Combination therapy with two or more agents having complementary mechanisms of action represents a type of incremental innovation that has extended the range of therapeutic options in the treatment of almost every human disease. Combination products also known, as fixed-dose combinations are combinations of two or more

active drugs produced in a single dosage form. They provide the advantages of combination therapy while reducing the number of prescriptions and the attendant administrative costs. The Indian laws have not been properly defined to grant marketing approvals of the fixed dose combinations (FDCs) by state or central drug controlling authorities. There is alarming increase in irrational FDCs in recent years and pharmaceutical companies manufacturing these FDCs are luring physicians to prescribe by unethical means. Unfortunately, the real contribution of combination products to therapeutics has been blurred by perceptions of inherent disadvantages. Considering these criteria it is essential to weed out the irrational combinations mushrooming in pharmaceutical industry at present.

Introduction:

All the formulations are meant for prevention or treatment of ailments and diseases, out of which only a few drugs are lifesaving and essential; rests of the drugs are substitutes for each other. The basic aim of the therapy is to treat a particular aliment with effective and safe drugs. Combination products also known as fixed dose combinations (FDCs) are combinations of two or more active drugs present in a dosage form1. More than one-third of all the new drug products introduced worldwide during the last decade were fixed dose combination (FDC) preparations. However, there is lack of statistical data for the developing countries, although, the trend seems to be the production and prescription of FDCs. The World Health Organisation (WHO) lists nearly 325 essential drugs, including only 19 of such drug combinations2. Whereas, the national list of essential medicines have 354 essential drugs, including 14 drug combinations. FDCs available for the treatment of various ailments range from nutritional deficiency to cardiovascular diseases. There are many popular FDCs in the Indian pharmaceutical market. However, the safety profile of the established drugs will alter when they are combined together. Maximum FDC preparations comprise vitamins; cough suppressants, anti-diarrhoeal, iron preparations, antacids, analgesics and tonics. USFDA is not convinced of the rationality behind combination products other than antitubercular, antihypertensive and anti-AIDS drugs which are life saving3. 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 hospitalisation, and decreased quality of life.

Rationale for Combination Therapy1

All drugs have unwanted side effects in addition to the desired therapeutic effect. The idea of combining two or more drugs with complementary modes of action is to produce additivity of the desired therapeutic effect but not of the side effects. Fixed

dose combinations are valuable only when they have been developed based on sound pharmacokinetic and pharmacodynamic criteria. As an example, at least five classes of drugs are commonly used to treat hypertension4: diuretics, beta-blockers, ACE-inhibitors, angiotensin receptor blockers, and calcium- channel blockers. The antihypertensive effects of an ACE-inhibitor and a calcium channel blocker, for instance, are additive, but these drug classes have different spectra of side effects, none of which are additive (although the spectrum can be broadened in a combination drug). Because the combination produces the same antihypertensive effect as higher doses of either constituent, the exposure to side effects is reduced and the therapeutic ratio is increased. The therapeutic ratio can be increased in certain instances by the phenomena of potentiation and cancellation. Potentiation is the synergistic effect on drug A by adding a dose of drug B without a therapeutic effect. An example is the combination of bisprolol or enalapril with a low dose of hydrochlorothiazide itself without antihypertensive effect. Cancellation is a phenomenon in which the adverse effects of one drug are nullified by the addition of a second (e.g., the hypokalemic effects of thiazide diuretics are counteracted by the slight hyperkalemic effect of an ACE-inhibitor).

Although combination therapy is typically a matter of two (or more) different classes of drugs with a common therapeutic effect, there are many types of combinations. In the combination of amoxicillin and clavulanate5, the latter compound acts by inhibiting bacterial degradation of amoxicillin, rather than having any direct therapeutic activity itself. This renders amoxicillin effective against strains that have become resistant through acquisition of a plasmid-borne gene encoding beta-lactamase. Similarly, in the combination of carbidopa and levodopa6, carbidopa itself has no beneficial therapeutic effect, but it inhibits the systemic decarboxylation and inactivation of levodopa before it crosses the blood–brain barrier and is converted to dopamine, the active metabolite that relieves the symptoms of Parkinson’s disease.

Advantages of Combination Products

Combination products have the advantages of combination therapy as well as advantages related to reducing the number of pills to be taken. Reduced administration costs stem from simplified packaging, fewer prescriptions, and fewer dispensing fees and co-pays. It has been known for many years that there is an inverse relationship between patient adherence and the complexity of the drug regimen7. Reducing the number of pills diminishes the complexity of the regimen, so that improved patient adherence is expected with combination products. Combination products make particular sense in the treatment of infectious disease, where partial adherence can lead to the development of drug-resistant strains and a threat to public health. The likelihood of a strain acquiring resistance to a constituent of combination therapy is zero if adherence is either zero or 100%, and reaches a maximum at

intermediate levels of adherence8. With combination products, patients take either all of the drugs or none of them, and the possibility of the serial development of strains resistant to each constituent drug taken individually is eliminated.

The disadvantages of FDCs8-11

·These fixed dose combinations can lead to polypharmacy.

·Dose of one ingredient can not been altered.

·Different pharmacokinetic properties can pose difficulty in frequency of administration and in case of development of an ADR.

·It is difficult to withdraw the suspected drug alone.

· The greater are the number of ingredients, the less likely the prescriber or the physician is to know what FDCs are and what their adverse reactions are. A combination makes it more difficult to pinpoint the offending agent responsible for the adverse reaction.

·Another drawback with FDCs is that they may lead to an ineffective dosage. In certain cases like heart failure, it becomes necessary to determine the strength of the dose against the appropriate end point. It is better to handle individual drugs rather than combinations in such life threatening conditions

·Some FDCs when combined lead to increased toxicity. For instance, the anti-TB drugs, streptomycin, kanamycin and capremycin cannot be combined, as they have the same side effects (oto and nephro-toxicity)

·If the biological half-life of different compounds of a FDC are different, it may considerably affect the pattern of drug availability in the plasma, and hence, the over all efficacy of the preparation (rifampicin fixed dose antitubercular formulations).

Drug control issues: Indian scenario 12

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 human being) banned 79 drug formulations from the year 1983 till date. Some examples are FDCs of vitamins with anti-inflammatory agents and tranquillisers, of anti-histamines with anti-diarrhoeals 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 DCGI. As per rule 122(E) of the Drugs & Cosmetic Rules, 1945, the same criteria holds good for US markets as well.

The safety of the combination drugs has to be thoroughly evaluated and there are considerations for the drugs that are already in the market as individual or single drug entity. However, the safety profile of the established drugs will alter when they are combined together. But many of the irrational combinations are popular and widely prescribed by physicians in our country. The combinations such as tetracycline and vitamin C, quinolones and nitroimidazoles and penicillins with sulfonamides are some of the examples of irrational FDCs. Such dubious FDCs entail financial burden, resistant strains of bacteria and increase in unwanted effects. The regulatory requirements for approval of combination products vary from country to country and there are no specific regulations in our country.

Fixed dose combinations in India.13-16

In India a variety of combinations of drugs are available which are not included in WHOs list of essential medicine and are irrational. Following are examples of some.

Pediatric formulations of Nimesulide + Paracetamol can induce severe hypothermia in small children and lead to shock. FDCs of Diclofenac + Serrapeptase do not offer any particular advantage over the individual drugs despite vigorous claims that Serrapeptase promotes more rapid resolution of inflammation. On the other hand, the patient is exposed to greater risk of gastrointestinal [GI] irritation and serious bleeding from unsuspected peptic ulceration. FDCs of quinolones and nitroimidazoles (e.g. Norfloxacin + Metronidazole, Ciprofloxacin + Tinidazole, Ofloxacin + Ornidazole) have not been recommended in any standard books, but continue to be heavily prescribed drugs in GI infections, pelvic inflammatory disease, dental infections, etc., to cover up for diagnostic imprecision and the lack of access to laboratory facilities. Such injudicious use of antibiotic FDCs can rapidly give rise to resistant strains of organisms, which is a matter of serious concern to the health care situation in our country. An important example is the emergence of Ciprofloxacin resistant Salmonella typhi strains, which have made treatment of typhoid fever a difficult and expensive proposition in India today.

In India, a variety of NSAID combinations are available, often as Over-The-Counter products. These combinations are the easiest way of selling two drugs when one (or even none) may be needed for the patient. These combination pills have now become the largest selling 'brands' of antiinflammatory/analgesic/antipyretic products. The

'single' drugs have almost become redundant and 'old fashioned'. There is no synergism when two drugs acting on the same enzyme are combined. Thus combining two NSAIDs or NSAID with analgesics like paracetamol does not and cannot improve the efficacy or potency of treatment. If at all, it only adds to the cost of therapy and more important, to the adverse effects.

Another most widely prescribed FDC's not having any rational basis are the multivitamin combinations and cough and cold remedies. WHO has deleted the combination of vitamins from its list with the comment that vitamins are considered part of nutrition and vitamin combinations should not be used indiscriminately. The cough mixtures contain expectorants; cough suppressants, antihista-mines, sympathomimetics, alcohol and other CNS depressants without any rational basis.

Conclusion:

As the wellbeing of a patient’s health lies in the hands of healthcare professionals and pharmacists, it is essential for them to get acquainted with the list of drugs which are irrational and banned by DCGI. In addition, they should keep themselves updated with the notifications issued by the DCGI to curb irrational fixed dose combinations. Moreover, joint efforts of regulatory authorities, healthcare professionals, researchers and pharmaceutical companies to formulate guidelines for the FDC’s will be beneficial in this regard. There should increased importance of a decision to withdraw the drug or its combinations from the market are taken care of by the pharmacovigilance committee in the country.

References:

1. Albert I. Wertheimer, Alan Morrison. Combination Drugs: Innovation in Pharmacotherapy.Pharmacol and Ther. 2002,Jan; Vol. 27 (1): 44-49.

2. http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf 3. Office of Combination Products, Food and Drug Administration,

USA: www.fda.gov/ oc/combination/21 CFR Part 3.2(e).4. Jayanti Panda, Tiwari P, Uppal R. Evaluation of rationality of some FDC: Focus

on antihypertensive drugs. Indian journal of Pharm sci, 2006, Sep: 649-652.5. Gilman AG, Rall TW, NiesAS et al (Eds); Goodman and Gillman’s The

Pharmacological Basis of Therapeutics, 8th edn. Pergamon Press, New York, NY,1990.

6. Bertram G. Katzung; Basic and Clinical Pharmacology, 9th edn. Mc Graw Hill. New York.2004.

7. Haynes RB. A critical review of the “determinants” of patient compliance with therapeutic regimens. In: Sackett DL, Haynes RB, Editors. Compliance with therapeutic regimens. BaltimoreJohns Hopkins University Press, 1976: 26-39.

8. Friedland GH, Williams A. Attaining higher goals in HIV treatment: the central importance of adherence. AIDS. 1999 Sept; 13 Suppl 1:S61-S72.

9. Hilleman DE, Ryschon KL, Mohiuddin SM, Wurdeman RL. Fixed-dose combination vs. monotherapy in hypertension: a meta-analysis evaluation.Journal of Human Hypertension.1999, 13: 477–483.

10.Patel V, Vaidya R,Naik D, Borkar P.Irrational drug use in India: A prescription survey from goa.J postgrad med. March 2005,51(1):9-12.

11.Saranjit Singh, Hemant Bhutani, Mariappan T.Quality problems of anti-tuberculosis fixed-dose combinations (fdcs): a way forward. Indian J Tuberc. 2006, 53:201-205.

12.S. K. Kulkarni. On the safety of nimesulide, a preferential COX-2 inhibitor. Current science. December 200,283(12): 1442-1443.

13.Sreedhar D, Subramanian G, Udupa. N. Combination drugs: Are they rational? Current science. August 2006, 91(4): 25.

14.Avijit Chakraborti. Fixed dose combinations in therapy. Express pharma.2007, 2 (19): 62-63.

15.Amitava Sen. Indian market's fixation with fixed dose combinations. Rational Drug Bulletin. Jan-mar 2002,12 (1): 1-2.

16.Sarkar C, Das B. Prescribing trend of fixed-dose drug combinations in a tertiary hospital in Nepal. Journal of Institute of Medicine. 2000, 22 (3 & 4): 53-58.

BAN ALL IRRATIONAL COMBINATIONS

Pharmabizz.comWednesday, March 21, 2001 08:00 IST P A Francis

The Centre last week issued a notification banning fixed dose combinations of diazepam with diphenhydramine hydrochloride for its harmful effects on humans. The notification also seeks to phase out 8 other fixed dose combinations by January 1, 2002 for their therapeutic irrationality. The number of formulations under these 8 categories of fixed dose combinations may run

into hundreds and are being marketed all over the country. These irrational drug formulations are being manufactured not only by small and unscrupulous elements in this industry but also by the big 'dadas' like Cipla, Ranbaxy, Glaxo SB, Wockhardt, RPG Life Sciences and Alkem. Probably the time of nine months is given for the phase out in consideration of the large number of such formulations circulating in the country. It is also possible that Drug Controller General of India (DCGI) may be expecting someone from the industry to challenge the phase out order as the stakes involved in this exercise is quite high for the manufacturers. Many of the established brands will have to be withdrawn from the market when the implementation of the order takes place. That is certainly going to be an unpleasant job especially for the big ones as it could straightaway hit their bottomlines. Some of them may be successful with the regulatory authorities in retaining their brand names by reformulating the product. But that decision has to come from the DCGI now and not from the state drug authorities as it used to be.

Safety and rationality of a drug or its combinations are extremely crucial in a country like India with a huge illiterate population and highly inadequate health infrastructure. Absence of ethics and moral standards amongst the medical practitioners, pharmaceutical industry and trade make the task of drug administration extremely difficult for the regulatory authorities. The growth and prevalence of thousands of irrational combinations of drugs in this country is a direct result of this total lack of concern by these three pillars of pharmaceutical sector. For a long time, there have been no serious attempts on the part of the Central regulatory authorities to bring discipline on this front. Drug companies could procure a manufacturing licence for any undesirable combination from the state drug authorities although a new combination of drugs is defined as a new drug as per the provisions of Drugs and Cosmetics Act. And permission to market any new combination of drugs should be granted by DCGI only. However, the recent initiative by the Union health ministry and the office of DCGI to weed out harmful and irrational combinations is indeed laudable. But the DCGI needs to be firm in handling this issue. It is right in banning combinations of diazepam with diphenhydramine hydrochloride. But combinations of diazepam with atenolol and propanolol are also equally irrational and harmful. There are no reasons to allow continuation of combinations like amlodipine with lozarten, amlodipine

with atenolol, ciprofloxacin with tinidazole, nalidixic acid with tinidazole, nimusalide with paracetamol, etc. A combination like nifedipine with atenolol is not allowed in many countries but in India it is being freely marketed.

Fixed dose drug combinations (FDCs): rational or irrational: a view pointChandler S Gautam and Lekha Saha

 Combination products, also known as fixed dose drug combinations (FDCs), are combinations of two or more active drugs in a single dosage form. The Food and Drug Administration, USA defines a combination product as ‘a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product’[1]. It is widely accepted that most drugs should be formulated as single compounds. Fixed ratio combination products are acceptable only when the dosage of each ingredient meets the requirement of a defined population group and when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety or compliance [2]. 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 [3]:

The drugs in the combination should act by different mechanisms. The pharmacokinetics must not be widely different. 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 recent 14th model list of essential drugs prepared by the WHO (March 2005) includes 312 formulation of which 18 are fixed dose drug combinations [4]. The

World Health Organization's (WHO) Model list of Essential Drugs provides examples of some rational FDCs such as [5]:

sulfamethoxazole + trimethoprim antitubercular FDCs like rifampicin + isoniazid, isoniazid + ethambutol,

etc antiparkinsonism FDCs like levodopa + carbidopa

Unfortunately, many FDCs being introduced in India are usually irrational. The most pressing concern with irrational FDCs is that they expose patients to unnecessary risk of adverse drug reactions, for instance, paediatric formulations of nimesulide + paracetamol. Nimesulide alone is more antipyretic than paracetamol, more anti-inflammatory than aspirin, and equivalent in analgesia to any of the NSAIDS alone [6], so efficacy gains are unlikely with added paracetamol. However, the patients may be subject to increased hepatotoxic effects from the combination. FDCs of diclofenac + serratopeptidase do not offer any particular advantage over the individual drugs despite the claim that serratopeptidase promotes more rapid resolution of inflammation [3]. On the other hand, the patient is exposed to greater risk of gastrointestinal (GI) irritation and serious bleeding from unsuspected peptic ulceration. FDCs of quinolones and nitroimidazoles (e.g. norfloxacin + metronidazole, ciprofloxacin + tinidazole, ofloxacin + ornidazole) have not been recommended in any standard books [7, 8], but continue to be heavily prescribed drugs in GI infections, pelvic inflammatory disease, dental infection, etc., to cover up for diagnostic imprecision and the lack of access to laboratory facilities. Such injudicious use of antibiotic FDCs can rapidly give rise to resistant strains of organisms, which is a matter of serious concern to the health care situation in our resource poor country. A glaring example is the emergence of ciprofloxacin-resistant Salmonella typhi strains which have made treatment of typhoid fever a difficult and expensive proposition in India today [3].In India, a variety of NSAID combinations are available, often as over the counter products [9]. These combinations are an easy way to sell two drugs when one (or even none) may be needed for the patient. The ‘combined’ pills are marketed with slogans like ‘ibuprofen for pain and paracetamol for fever’ and ‘ibuprofen for peripheral action and paracetamol for 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 [10] 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 [9]. 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 [3]. Some

such fixed drug combinations are now banned in India [11].

Over the years the Indian Drug Control Authority has issued banned notifications on many FDCs like analgin + pitofenone, vitamins B1 + B6 + B12, cyproheptadine + lysine, etc. [11]. But are these measures sufficient? Obviously not, since these notifications have not deterred manufacturers from coming out with new irrational FDCs. At this crucial juncture, when the global community, represented by WHO, is making an all out effort to propagate the concept of essential drugs amongst consumers throughout the world, our official stance could be viewed as too meager. India, as the world's second most populous country, should demand a more rational approach and not pay mere lip service to the global campaign.

Irrational FDCs also impose unnecessary financial burden on consumers. Medical practitioners who patronize such combinations could be the centre of controversy when subjected to litigation in consumer forums, as these combinations do not find mention in standard text or reference books and reputed medical journals. Pharmaceutical manufacturers, however, continue to reap the benefits of huge sales, and therefore continue to promote combinations with vigour.

The time has come for all practitioners and consumers to raise this matter vociferously through all possible avenues. Drug regulatory bodies should take urgent action to mitigate the free flow of irrational FDCs.

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REFERENCES1. Sreedhar D, Subramanian G, Udupa N. Combination drugs: are they rational? Curr Sci.2006;91:406.

2. World Health Organization. The use of essential drugs. WHO Technical Report Series 825. Geneva: World Health Organization; 1992.

3. Amitava S. Indian market's fixation with fixed dose combinations (Editorial) Rational Drug Bulletin.2002;12:1.

4. World Health Organization. The Use of Essential Drugs. WHO Technical Report Series 933.Geneva: World Health Organization; 2006.

5. World Health Organization. The Use of Essential Drugs. WHO Technical Report Series 850.Geneva: World Health Organization; 1995.

6. Gautam CS, Aditya S. Irrational drug combination: need to Sensitize undergraduates. Ind J Pharmacol. 2006;38:167–70.

7. Margaret AP, Samuel LS., Jr . Chemotherapy of protozoal infections. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 11. New York: McGraw-Hill; 2006. pp. 1049–50.

8. Rosenthal PJ. Antiprotozoal drugs. In: Katzung BG, editor. Basic and clinical pharmacology. 9. Boston, MA: Mc Graw-Hill; 2004. pp. 875–8.

9. Gulhati CM. Monthly index of medical specialities, India. MIMS INDIA. 2005;25:81–94.

10. Burke A, Smyth E, Gerald GAF. Analgesic-antipyretic agents; pharmacotherapy of gout. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's the Pharmacological Basis of Therapeutics.11. New York: Mc Graw-Hill; 2006. p. 685.

11. Tripathi KD. Essentials of medical pharmacology. 5. New Delhi: Jaypee Brothers; 2004. Appendix 2. Drugs and fixed dose combinations banned in India; pp. 847–8.

Articles from British Journal of Clinical Pharmacology are provided here courtesy of

British Pharmacological Society

5 Dangerous Drug Combinations You Need to AvoidIf you're mixing supplements and prescription pills, you may be getting a risky blend of medicationsBy DEBORAH KOTZPosted: December 23, 2008Note to seniors (and anyone else) mixing prescriptions with painkillers and/or their favorite dietary supplements: Don't do it until you check with your doctor to make sure they don't interact to cause you harm. A new study published today in theJournal of the American Medical Association shows that 1 in 25 people in their late 50s and older is risking dangerous drug interactions by mixing, for example, the blood thinner warfarin with garlic pills.

That's right, garlic pills are drugs. So, too, are potassium and niacin supplements. At least you should think of them that way, says study coauthor Stacy Tessler Lindau, an assistant professor of medicine-geriatrics at the University of Chicago School of Medicine. Some of the most common drug-mixing mistakes made by patients participating in the study:

warfarin and simvastatin (Zocor): increased risk of bleeding problems like bleeding ulcers, rectal bleeding, and easy bruising; also increases the possibility of statin side effects like muscle pain and muscle tissue death. (Statin-related pain is a serious problem; here are seven reasons not to dismiss it.)

niacin and either atorvastatin (Lipitor) or simvastatin (Zocor): increased risk of muscle pain or muscle tissue death

lisinopril (Zestril, Prinivil) and potassium: increased risk of hyperkalemia, a dangerous elevation of potassium that can lead to heart attacks or even death

ginkgo and aspirin: increased risk of bleeding problems garlic pills and warfarin: increased risk of bleeding problems

Given that more than half of older adults take five or more prescription drugs, over-the-counter medications, or dietary supplements every day, the likelihood of mixing at least two substances that shouldn't be mixed is pretty high.What to do?

Try to obtain all your prescription medications through the same pharmacy or pharmacy chain . A computer software program will cross-check your meds to make sure none of them cause dangerous interactions with the others. Unfortunately, there's no universal database shared by all pharmacies. There's also no way to log in all the supplements and OTC remedies you're taking.

Purchase all over-the-counter products at the pharmacy counter of the drugstore. "This will remind you to check with the pharmacist before you make the purchase to make sure you can safely take it with your other medications," says Lindau.

Tell your doctor about any supplements you're taking. Many still don't ask, so the onus is on you to reveal whatever you're taking. You can also do a quick check of the government-run Medline Plus database   to see which drugs and supplements don't mix.Here are four more ways to avoid dangerous drug errors and which foods not to mix with drugs.

Irrational drug combinations in India

CIMS lists more than 100 irrational combinations which are not approved in any developed country but are being marketed in India.

Title of paper: Irrational drug combinations: Need to sensitize undergraduatesAuthor: Gautam CS, Aditya SDepartment of Pharmacology, GMCH, Chandigarh - 160 032, India

How to cite this article:Gautam CS, Aditya S. Irrational drug combinations: Need to sensitize undergraduates. Indian J Pharmacol 2006;38:169-170

How to cite the source URL:Gautam CS, Aditya S. Irrational drug combinations: Need to sensitize undergraduates. Indian J Pharmacol [serial online] 2006 [cited 2006 Jun 13];38:169-170. Available from: http://www.ijp-online.com/article.asp?issn=0253-7613;year=2006;volume=38;issue=3;spage=169;epage=170;aulast=Gautam

Prescribing fixed dose drug combinations has become the "in thing" in medical practice. Using the excuse of better patient compliance, many doctors, both in private as well as government prescribe irrational fixed dose drug combinations. Quite a few infectious diseases are becoming resistant to treatment with a single drug. With the escalating cost of drugs, there is poor drug compliance, which further magnifies the problem, both for the prescriber as well the patient. Manufacturers of drugs having quickly tuned in to the potential golden egg, are marketing fixed dose drug formulations for various diseases.

Even though use of combinations of drugs is common practice, the selection of optimal dose and optimal combination has remained largely a matter of trial and error. The basis of many fixed

dose drug combinations being taught to the undergraduate medical students and also being prescribed popularly, appears to be irrational to pharmacologists.

CIMS lists more than 100 irrational combinations which are not approved in any developed country but are being marketed in India. This fact has to be taught to undergraduate medical students in their formative years of learning so that once they address medical ailments like malaria, tuberculosis, AIDS, hypertension, etc. they should be more logical in selecting appropriate drug combinations and should not be swayed by marketing tricks and false claims made by the pharmaceutical industry. The pharmacological basis of combining each ingredient in the formulation should be taught. Selection of P drugs, rational drug use, use of rational drug combinations and ethical laboratory practices should be inculcated in the student's curriculum during their clinical training.

Fourteenth WHO model list of essential medicines (March 2005) contains only 18 approved drug combinations, whereas in India, there are innumerable examples of irrational drug combinations, which are easily available and can be bought without necessarily giving a prescription. [Table - 1] This issue has to be urgently addressed by us, pharmacologists, as the magnitude of the problem is increasing.

Opinion - Pharmaceuticals

Irrational drugs — Living with the menaceP. A. FRANCISEven as the law against irrational Fixed Dose Combinations has been around since 1988, precious little has been done to prevent the proliferation of absurd FDCs. The nation is paying the price for belated action, says P. A. FRANCIS.

The pharmaceutical industry has been manufacturing and marketing fixed dose combinations (FDCs), many of them irrational and harmful for the last two decades. Initially not many in number, today they are in several thousands and a large number of them have no therapeutic rationale.

The uncontrolled growth of such combinations in India more often than not has been the brainwave of marketing heads of pharmaceutical companies. Responding to the pressure for newer products, marketing heads of pharma companies used to invent combinations of two or more drugs, often launched without an assessment of their therapeutic benefits.

Medical experts the world over, have expressed serious concern over the marketing of an increasing number of drug combinations by pharmaceutical companies, particularly in developing countries. The basis for this concern lies in the universally accepted practice that a drug combination is technically a new drug entity and that its marketing can be allowed only after its safety and efficacy are adequately established.

While combining two drugs, the efficacy and bioavailability of the two drugs undergo a change on account of the reactions between these chemicals. Therefore, detailed clinical trials and bioavailability studies have to be completed before such products are allowed to be marketed. For serious ailments such as TB and AIDS, patients’ intake of more than one drug at a time for longer treatment period is critical and drug combinations are justified for the sake of patient compliance. Unfortunately, that is not the case with most of the FDCs currently marketed in India.

Arming the law

Since FDCs are considered new drugs, the Union Health Ministry amended the Drugs & Cosmetics Rules in 1988 to address this new development. Rule 122 (E) (c) of the Drugs & Cosmetics Rules, says all new drugs have to be approved by the Drug Controller-General of India (DCGI) for marketing in the country after submission of all relevant pre-clinical and clinical trial data. The amendment thus made it abundantly clear that the state drug authorities have no power to issue product licences for FDCs. Most of the drug control departments in the states and Union Territories in any case do not have the expertise or facilities to assess the merits and demerits of drug combinations.

That amendment was observed more in the breach; state licensing authorities (SLAs) continued to permit FDCs over the years without insisting upon the statutory requirements of pre- clinical and clinical trials.

At the same time, the central drug control administration, the office of DCGI that should have assumed this responsibility and acted to check the problem of irrational combinations once the amendment had armed it with the required powers, did almost nothing. Combinations multiplied in the market.

Using the law

In November 2001, the DCGI for the first time issued a directive to state drug controllers expressly prohibiting them from issuing any more licences for combination drugs; state drug control departments continued to ignore the DCGI order.

In July 2004, the DCGI got tougher; it asked the state drug controllers to withdraw all manufacturing licences issued by them for drug combinations after May 2002. That directive too was ignored.

Nearly two decades after the amendment that armed the DGCI with powers to check FDCs, a meeting of the Drug Consultative Committee composed of MPs, Health ministry and DGCI officials held a meeting in July 2007 and reviewed the problem of irrational combinations.

After the meeting, the DCGI once again issued a directive on August 14 to the state drug controllers asking them to start preparing for the removal of irrational combinations from the market. Most state drug controllers ignored the directive.

At long last

In October, the DGCI moved where states feared to tread. On October 26, the DGCI met state drug controllers and industry representatives the next day in Chandigarh. A list of 294 combinations was prepared and classified into different categories based on their irrationality and absurdity with the help of 100 pharmacologists.

Before meeting industry, the office of the DGCI briefed the state drug controllers about the modus operandi of removing these questionable products from the market. In the meeting with the industry representatives subsequently, the DCGI asked them to stop manufacturing all the 294 drug combinations forthwith.

He also wanted products falling under 144 combinations to be removed from the trade channels. In the case of products under the remaining 150 combinations, the DGCI was willing to allow sales of existing stocks but insisted their production cease. In the meantime, he promised a review of the rationality of these combinations within 40 days.

The sins of delay

The DGCI list of irrational products spans major therapeutic categories such as orthopaedics, anti microbial, gastrointestinal and cardiovascular. In orthopaedics alone, there are more than 360 products marketed by top companies such as Dr Reddy’s, Alkem, Zydus Cadila, Cadila Pharma, Nicholas Piramal, Lupin, Glenmark and others. Most of these combinations are of Chlorzoxazone, paracetamol and Diclofenac sodium or ibuprofen.

In the gastrointestinal category, there are 248 irrational products marketed by the same set of companies and others such as Alembic, Ipca, Emcure, Cipla, Intas, Micro, Unichem and Merck.

In this category, a large number of products are of ofloxacin and tinidazole or metronidazole. There are also 200 anti-microbial products classified as irrational belonging to again the same set of companies along with a number of medium and small enterprises.

Industry leaders have opposed the DCGI’s stand; a joint memorandum of all the major pharma associations to the union ministry of health threw the ball back in the drug

authorities’ court. It pointed out that the amendment of the Drugs & Cosmetics Rules in 1988, the State Licensing Authorities were required to obtain NOCs from the DCGI before issuing manufacturing licenses for new FDCs. But, the SLAs ignored this stipulation and continued to grant manufacturing licences for combination products.

Associations are of the view that the office of the DCGI was fully aware of this practice. Some SLAs had even brought the matter to the notice of the successive DCGIs, but they had all ignored the alerts thus tip-toeing around the rule. In short, the memo suggested the office of DCGI is also responsible for the current state of affairs and he should, therefore, give industry sufficient time in this matter.

The last resort

Since the DCGI is not in a mood to listen to them, some of the manufacturers from the south have approached the Madras High Court and obtained a stay against the DCGI move early November. The whole action plan of DCGI is in a fix now. Weeding out irrational drugs from the market can commence only after DCGI vacates the stay. This may take a few days or weeks.

For pharmaceutical units, discontinuation of products under 294 combinations would mean loss of business worth nearly Rs 5,000 crore. It is a business they have built over the years by cultivating physicians and the retail trade. They may not let go that business easily; equally the DCGI is convinced about his stand.

Just how the crying need to clean up this mess of irrational and unsafe products for the patient community and the nation’s image is met, only time will tell.

(The author is editor of ‘Pharma Biz’, a leading industry journal.)

Title: Drugs & Alcohol: Simple Facts About Alcohol-Drug CombinationsAuthor: Christina Dye

Publisher: Do It Now FoundationPublication

Date: March 2010

Catalog Number: 121

..The Simple Facts

There are hundreds of studies, crammed with millions of words, examining the subject of alcohol-drug interactionsfrom every conceivable angle. Still, if you had to summarize them all, you could do it with a single word: Don't.

Because the simple fact is that alcohol is a drug and, like every other drug, has potential for risks, both

large and small.

And when it's used with other drugs, the risk index for booze jumps right off the chart. Just consider:

Government reports rank alcohol-drug combinations as the leading cause of drug-related deaths in the United States, and have for decades.

Complications caused by drinking-and-drug interactions sent 524,000 Americans to hospital emergency rooms in 2008 alone for treatment.

Those are pretty simple facts. Want another?

Then try this one: A majority of all the poisonings and overdoses that take place every year are accidents, plain and simple.

They involve normal, everyday people using normal, everyday medicines-folks who just didn't realize that Drink A (a Tequila Mockingbird, say, from the local Mai Tai Hut) interacts with Drug B (Flagyl®, for example) to produce Effect C (cramps, vomiting) until after it did.

That's why we've put together this pamphlet. Because the hardest fact to swallow is this: Most drug-and-alcohol mishaps could be avoided if the people involved only knew what might happen before it did happen.

The fact that they often don't only makes the rest of what we'll be talking about in this pamphlet that much more critical.

Sound simple enough? Good.

Stick around. It keeps getting simpler.

..Simple Fact #1: Drinking and downers don't mix.

Simple Fact #1 flows from Funny Fact #1 (as funny as these facts ever get, anyway) of this pamphlet, which is that one and one doesn't always equal two.

Oh, it does on a calculator, but that's because calculators can't calculate all the possible outcomes of all the dumb things that people do.

And one of the dumbest things that people ever do centers around one of the most critical times that one and one doesn't equal two: When somebody adds the effects of booze to other depressant drugs.

That's because alcohol is a depressant, just like tranquilizers and sleeping pills. And like other downers, it slows bodily functions, including breathing and heart rate. And when people drink enough (or combine too much alcohol with too many downers), things slow down so much that they stop altogether.

Why? Because alcohol and downers compete for the same system of liver enzymes that break down drugs and flush them from the body.

That means when two or more downers are in play at the same time, the liver can't handle the load.

Result: Drug molecules are reabsorbed and recirculated throughout the body.

That's when problems really kick in.

The scientific name for this process is synergism. It means that the effects of drugs taken together can be very different than the effects they produce solo.

The difference can be like night and day. In fact, it can even determine whether a person makes it through the night to ever see another day.

..Simple Fact #2: Smoking doesn't mix with anything.

Sniff the air inside almost any bar and you'll immediately bump into one of the most common alcohol-drug combinations: booze and cigarettes.

And according to recent studies, it may also be one of our most dangerous.

Because researchers now believe that drinking increases absorption of cancer-causing tobacco by-products in the body. Recent studies have shown a greater risk of cancers of the mouth, neck, and throat among drinkers who also smoke. And alcoholics who smoke heavily suffer higher levels of these cancers than heavy smokers who don't drink.

Risks linked to smoking and drinking don't stop with cigarettes, either. Today, scientists warn that an increased risk of cancer may also be linked to marijuana and alcohol, since pot contains many of the same cancer-causing chemicals as tobacco.

Long-term risks aside, though, alcohol and pot pose a multitude of immediate problems, with effects that can turn a night out on the town into a night of just being plain out of it.

For one thing, each can reduce coordination and concentration and slow reaction time, all critical skills if you're performing complex tasks -- driving, for example.

In addition, both booze and pot can impair visual "tracking" ability, making it harder for a smoker or drinker to follow a moving object or perceive changes and movement in peripheral vision.

Those are just some of the factors that make piling a pot high on top of a booze buzz potentially risky.

And the risk is needlessly compounded when a stoned drinker does something really dumb -- like sliding behind the wheel of a car.

..Simple Fact #3: Medicine doesn't make it as a mixer.

A hundred years ago, alcohol was the number one all-purpose cure-all in the country, the "secret" ingredient in any number of patent medicines and prescription potions.

Today, alcohol isn't considered a cure or treatment for anything, or used at all medicinally, except as

an ingredient in some cough and flu preparations.

Because the fact is that alcohol can alter the way medicines work and often blocks or decreases their therapeutic action.

Antibiotics (a group that includes such common drugs as penicillin and tetracycline) tend to lose their effectiveness when mixed with alcohol.

Other medications (including such drugs as metronidazole, or Flagyl®) can interact violently with alcohol, producing a set of unexpected (and unwelcome) side effects, such as cramps, vomiting, and headaches.

And those kinds of effects can be (or fast become) a bigger problem than the original.

Want to avoid problems altogether? Just do the math -- and remember to subtract, rather than add.

..Simple Fact #4: Up isn't always the opposite of down.

The best recipe for sobering up is hot coffee and a cold shower, right?

In a word, no. In fact, dosing a drunk with caffeine, the main stimulant in coffee, is little more than a time-honored waste of time.

After throwing down a few cups of Brazil's Best, a drinker may be wide awake -- but every bit as drunk as before. 

One study even suggests that following up a liquor-ish late-night with an early-morning cup of joe may slow response time even more than booze alone.

Stronger stimulants, such as cocaine or amphetamines, don't straighten out a drinker, either. (They can even make things worse: Check out the "Simple Fictions" listed in the box below for more.)

Even worse, they can trick users into believing that they're speeding toward sobriety.

Why? Because stimulants temporarily mask the depressant effects of liquor, giving drinkers a false sense of security without improving coordination or concentration, or driving skills, for that matter.

Alcohol/stimulant combinations cause other problems, too, including increased blood pressure, tension, and jitters.

These effects may not always be serious in themselves, but they can contribute to a number of potential problems that nobody wants or needs.

..Simple Fact #5: It's easier to prevent problems than fix them.

The truth is that there's no real trick to avoiding problems with drugs and alcohol.

In fact, staying out of trouble is basically a simple matter of applying common sense about what you put in your body and when.

It's an old adage, but it's as true now as ever: An ounce of prevention can prevent a ton of pain.

To reduce your risk of problems with the drugs that you take (or may be taking in the future), always remember:

Tell your doctor about any drugs you're taking. Follow instructions carefully. Be sure you understand how and when to take any drug

and that you're aware of potential side effects. If you drink, find out if it's safe to drink while taking a prescription drug. If you're not

sure, assume that it's not okay-and don't do it.

Because the final simple fact about alcohol/drug combinations is that staying alive and staying healthy starts with staying smart.

Accidents can happen. But they don't happen as often to people who are smart enough to avoid them.

And that's the simplest fact of all. 

..Sidebar1 | Rumors & Reality

Rumor: Beer and wine cause fewer "serious" problems than hard liquor.

Reality: All alcoholic beverages contain about the same amount of alcohol. Beer and wine contain more water, but have the same potential for problems.

Rumor: Cocaine and alcohol cancel each other out, enabling party people to stay straight longer.

Reality: They might think they're straight, but they're not. In fact, the body converts the breakdown products of cocaine and alcohol into a different chemical, cocaethylene, which is twice as deadly as cocaine is all by itself.

Rumor: If you take aspirin before drinking, you can avoid a hangover.

Reality: Aspirin increases the stomach's absorption of alcohol, particularly when taken an hour or so before drinking. If anything, it increases the odds of a hangover.

..Sidebar 2 | Bomb Squad: Booze Lights Their Fuse

Drug Class Trade Name(s) Effects with Alcohol

Anti-Alcohol Antabuse® Severe reactions to even small amounts: headache, nausea, convulsions, coma, death.

Antibiotics Penicillin, Cyantin® Reduces the drugs' therapeutic effectiveness.

Antidepressants

Elavil®, Prozac®, Tofranil®,Nardil®

Increased central nervous system (CNS) depression and blood pressure changes. Combination use of alcohol with MAO inhibitors can trigger massive increase in blood pressure, resulting in brain hemorrhage and death.

Antihistamines Allerest®, Dristan®

Drowsiness and CNS depression. Impairs driving ability.

Aspirin Anacin®, Excedrin®

Can intensify alcohol's effects. Irritates stomach lining. May cause gastrointestinal pain, bleeding.

DepressantsValium®, Ativan®, Xanax®

Dangerous CNS depression, loss of coordination, coma. High risk of overdose and death.

Narcotics heroin, codeine, Darvon®

Serious CNS depression. Possible respiratory arrest and death.

Stimulants amphetamine, cocaine

Masks the depressant action of alcohol. May increase both blood pressure and physiological tension. Increases risk of overdose.

EDITORIAL

Year : 2007  |  Volume : 39  |  Issue : 5  |  Page : 217

 

Irrational combinations: No consideration for patient safety

Many articles have been written on the dangers of fixed dose combinations (FDC). The topic has been fiercely debated, because there is a need to weed out such combinations from Indian market for the safety of patients. But no pharmaceutical company has voluntarily stopped selling such combinations in India; on the contrary, they have continued to introduce more of such irrational combinations. We must welcome the initiation of action from DCGI's office. We needed somebody like Dr. Venkateshwarulu, the present DCGI, to take the bold step of issuing notices to withdraw those FDCs that have no therapeutic rationale and poor safety profile. He made an emotional appeal to the state drug authorities in the recently concluded Chennai meeting. From this one can get an idea of the reluctance of the state authorities to act on this deadly menace of FDCs in our country. 

Most of the combinations which are marketed by companies are permitted by the state drug authorities, which is in clear violation of the law in the first place. The new combinations are termed 'new drugs' as per the Drugs and Cosmetics Act (Rule 122 (E)); they must, therefore, undergo clinical trials and safety studies to qualify for entering the market.

Recently, the Indian Drug Manufacturers' Association (IDMA) has decided against going to the courts, fearing an adverse ruling. This is a clear indication that many companies know that their combinations are useless-if not actually harmful-and have no scientific rationale behind it. An industry which boasts of great growth is not bothered about the safety of its own customers-the patients who consume those drugs. It is not just the pharmaceutical companies that are to be blamed for this irresponsibility and greed. We also need to see the other side of the coin-the doctors, who prescribe such combinations every day without questioning their rationale. Doctors need to play an important role in avoiding such irrational combinations, which have no clinical trial and safety data to justify their availability in the market and which may put patients' lives in danger. Such combinations can be fatal at times (mint and coke produces a blast and death, which is a silly combination).

Pharmaceutical companies must behave in an ethical way in future and conduct detailed studies on such combinations. A pharmacokinetic drug interaction study is a must besides investigation of the safety profile. The DCGI office must put all the new combinations under a pharmacovigilance program for at least three years before giving them final marketing authorization. All the existing marketing authorizations must be cancelled at once and a surveillance program should be instituted. If the pharmaceutical company produces appropriate safety information by installing a good pharmacovigilance program for their product, then final marketing authorization must be issued. If there are any adverse events reported during this surveillance program, then the product must be withdrawn immediately, with appropriate patient compensation for the adverse events that occur. 

Rational combinations can be of immense help to the health care program. These combinations may improve the quality of life for many. Such combinations (for example, antitubercular and antiretroviral combinations) are needed very urgently for many diseases. 

I am sure some of the silly combinations will be off the shelf by the time I complete this editorial. Reworking on the above issues to provide the best combinations would restore the confidence in pharmaceutical companies, give assurance to regulatory people and, above all, make available better medicines for patients. 

  Editorial

NIMESULIDE REVIEW NOW?

Pharmabizz.comWednesday, October 09, 2002 20:00 IST P A Francis

A newspaper report last week had indicated that the adverse drug reactions of

nimesulide will be reviewed by the Drug Controller General of India. The report said that the move by the DCGI's office is in the wake of certain ADR reports of the drug and subsequent withdrawal of nimesulide from some of the European markets, Canada and Australia. The fact of the matter is that the drug has not been in use in these countries for some years. Nimesulide is reported to be inducing a high proportion of severe adverse hepatic reactions compared with other non-steroidal anti-inflamatory drugs (NSAIDs). According to researchers of Zurich University Hospital, hepatotoxicity represents an important risk factor in nimesulide usage. The drug has thus been banned in Spain and Finland last year. The newspaper report that a ban on the use of nimesulide in these countries is thus not a recent one. The DCGI has been aware of the adverse reactions of nimesulide for some years after it was cleared for marketing in India in the early nineties. In fact, Pharmabiz has brought this matter to the notice of the DCGI a year ago. If a review of the ADR of the drug has started now in the country, as claimed by the DCGI in the newspaper report that can only be described as an extremely delayed action on the part of a responsible government office. Inaction and delay in banning or restricting the use of harmful drugs by the regulatory authorities after they have shown serious adverse reactions is becoming a matter of serious public concern. 

There are more than 80 brands of nimesulide currently marketed in India today with no restrictions on their sales. The total market for single ingredient nimesulide brands is about Rs 250 crore and the top brand, Nise, of Dr Reddy's alone has sales of Rs 60 crore. Besides this, there are a dozen irrational combinations of nimesulide with paracetamol floating in the market. The licences for the manufacture of these irrational combinations were issued by various state drug authorities since 1998 despite specific guidelines from DCGI's cautioning about its irrationality. It is surprising that no action has been initiated by the DCGI office to weed out at least these irrational combinations even after four years of their existence in the market. It may not be always possible for the regulatory authorities to completely assess the harmful and other adverse effects of a new drug before marketing permission is granted. That is why even in the US there are cases of withdrawal of several new drugs in recent years shortly after marketing permissions are granted. But, withdrawals of harmful drugs are effected with a proper system of post

marketing surveillance in these developed countries. The Union health ministry needs to address this issue of withdrawal of harmful drugs and their combinations from the market with no further delay. Machinery for monitoring ADR of new molecules and their combinations should be first in place for this.

What are Vasporin, Ciprofloxacin and Voltaron used for?

Friday, 17 November 2006

Answered by: Dr. Chandra M. Gulhati Editor, MIMS, New Delhi

Q. The doctor has advised me to take Vasporin, Ciprofloxacin and Voltaron. What are the uses of the above drugs? I get pain in the knees due to which I can't sleep. What am I suffering from?A.  Vasoprin is a Fixed-Dose Combination of two medicines: isosorbide mononitrate and aspirin. It is irrational combination not permitted in any advanced country. Isosorbide mononitrate is used in heart patients for angina. Aspirin is used to make the blood thinner. However 75 mg to 80 mg of aspirin is normally used while Vasoprin contains 150 mg which can produce more side effects without any benefit to the patient. Voltaron contains diclofenac sodium, a potent pain killer. Ciprofloxacin is an antibacterial given to control infection. It is a chemical name, not a brand name. You have not given the name of others. Your doctor should tell you the diagnosis for which a heart medicine, an antibiotic and a potent pain-killer are being given. Since all the medicines are for different indications, I cannot tell you why they are being given. Your attention is invited to the following comments: General statement on selection of brands: There are scores, sometimes hundreds, of brands of the same medicine. Against about 300 pharmaceutical manufacturers in western countries like Britain, there are over 20,000 producers in India that market more than 40,000 brands. Most manufacturers do not have quality testing laboratories. Hence selection of brands is important. Many companies give incentives to prescribers to patronise their products. Patients should check the reputation of manufacturers before consuming medicines. Fixed-Dose Combinations (FDCs): Medicines are discovered individually and are supposed to be taken separately. A huge number of irrational, illegal combinations of drugs are being sold in India; quite a few without mandatory approval of the Drugs Controller General, India (DCGI). Except in a few cases (such as TB medicines), it is always better to take medicines separately so that dosage can be adjusted and side effects monitored.

Read more at

:http://doctor.ndtv.com/faq/ndtv/fid/10048/What_are_Vasporin_Ciprofloxacin_and_Voltaron_used_for.html?cp

EDITORIALIrrational fixed-dose drug combinations: a sordid story of profits before patientsC M Gulhati Anyone with even an elementary knowledge of medicine knows that, ideally, drugs should be administered as single molecules based on the specific requirement of each patient. This enables the prescriber to select specific  drugs in specific doses for specific durations. Only under exceptional circumstances are fixed dose combinations (FDCs) allowed. These are when (a) two or more drugs have a synergistic action, i.e. the combination acts to achieve a better therapeutic response than the individual drugs alone; (b) there is corrective action, and one drug acts to reduce the incidence and/or severity of adverse effects caused by the other; (c) two or more molecules are normally needed and taken by the patient concurrently - provided the dosage of each drug does not need to be individualised, or (d) prescribing two or more drugs separately could result in one of them not being ingested, and this would adversely affect the patient's health. Even under such situations care has to be taken to ensure that there are no adverse interactions between the combined drugs, that the pharmacological behaviour (absorption, duration of action, elimination) is not grossly different, that the withdrawal of one of the agents does not lead to withdrawal symptoms and in any event sub-therapeutic doses are never used. Conversely medicines cannot be mixed if side effects are additive or they belong to the same group with similar mode of action, such as two NSAIDs. Are these precise and scientifically sound guidelines being followed in permitting the combination of drugs in our country? Certainly not. All sorts of bizarre combinations have flooded the market. Many of them not only harm the patients, they can also damage the health of entire communities in the future by promoting the emergence of drug-resistant strains of micro-organisms. Take the example of combining quinolones (e.g. ciprofloxacin) with imidazoles (e.g. tinidazole). This combination is widely used, overused and misused for diarrhoea. Since most cases of diarrhoea are due to viruses, suboptimal use is giving rise to quinolone-resistant strains of typhoid germs. Manufacturers' main motive behind mixing drugs is, of course, to generate prescriptions and make profits. One can hardly expect anything else if there are over 17,000 pharmaceutical manufacturers, some 40,000 brands but only around 450 basic medicines. When atenolol does not generate enough sales, it is mixed with alprazolam to create an expensive 'novel' product. In the absence of research, the pharmaceutical industry in India has been reduced to a purely commercial activity in which marketing is the name of the game. It is no wonder that the basic principles of pharmacology get pushed to the background. As a result we have combinations such as nimesulide with paracetamol (both with hepato-toxic additive adverse effects); diclofenac (taken three times daily) with famotidine (taken once daily); mebendazole (taken twice daily for three days) with pyrantel (taken as a single dose), atenolol (taken once daily) with plain nifedipine (taken two-three times daily), and so on. Cisapride is combined with omeprazole so that a patient who requires just omeprazole, a relatively safe medicine, is also made to consume cisapride, a far more dangerous drug which is banned in western countries. 

Some of the most absurd fixed drug combinations are available in India. A few examples: nimesulide, paracetamol and tizanidine; amoxycillin,probenecid and tinidazole; diazepam, antacids and oxyphenonium. Over 70 dangerous FDCs are being sold in India under more than 1,000 brand names. Who is responsible for this mess of mixing incompatible medicines? We must blame the total lack of accountability of the drug regulatory apparatus, and the existence of parallel drug control centres in our country. All new molecules have to be approved by the Drugs Controller General, India (DCGI). Once a new molecule is licensed, the state drug controllers take over and monitor pharmaceutical manufacturing facilities located in their own jurisdictions. Legally, when two or more individually approved drugs are combined, the mixed medicine is deemed to be a 'new' product and hence requires DCGI approval. In practice, state drug controllers merrily go on licensing such combinations -- even though they do not have the legal powers to do so. Once one state drug controller approves a combination, it can be sold all over the country. The result: a patient in, say, Maharashtra consumes a drug that is neither approved by the DCGI nor by the Maharashtra drug controller but by a drug controller in, say, Assam! Unless state drug controllers are made to obey the law, no improvement can occur. The DCGI is no less culpable. In a federal set-up he may hesitate to move against erring state controllers but he has the power to ban such illegal combinations. He has failed to do so. If the Central Government does not move quickly, the day is not far off when courts will be compelled to move in to protect the health of the people.

India has become a dumping ground for banned drugs, Painkiller, Depression, Pharmaceutical

Many spurious drugs that have been banned, withdrawn or marketed under restrictions in other countries, continue to be sold in India. The pharmaceutical companies and defaulters are playing with the lives of thousands of people who are not aware of the harmful effects of the drugs they sell.

Life, it seems, comes cheap for the health officials of our country. Otherwise how else would you justify the existence of drugs withdrawn elsewhere in the world but still sold and prescribed in India?

"More than 60,000 branded formulations are available in India. These preparations contain either single drug or drugs in fixed dose combination (FDC). All formulations are used for treatment or prevention of diseases. Out of it only few drugs are lifesaving and essential drugs, otherwise maximum of them are available as alternative or substitute to each other."

The safety of the combination drugs has to be thoroughly evaluated and there are considerations for the drugs that are already in the market as individual or single drug entity. However, the safety profile of the established drugs will alter when they are combined together. There was alarming increase in irrational FDCs in recent years and pharmaceutical companies manufacturing these FDCs are luring physicians to prescribe by unethical means. This may be due to the implementation of product patent regime where the mediocre companies find various alternatives to sustain themselves in the market place and combination products for newer indications play a major role. The total number of essential drugs mentioned in the 14th list of essential medicines by WHO is 312, out of which only 18 are fixed dose combinations. But many of the irrational combinations are popular and widely prescribed by physicians in our country.

India has become a dumping ground for banned drugs. The business for production of banned drugs is blooming and because there are more consumers here and all illegalities are duly obeyed. The

irony is that very few people know about the banned drugs and consume them unaware, causing a lot of damage to themselves. The issue is severe and we must not delay in spreading the warning message to the offenders and innocent people.

As big time business enterprises and small time defaulters, pharmaceuticals have been growing in every direction. There are few provisions for a proper check and control of spurious drugs in Indian markets. Worst than that is the little knowledge and slapdash attitude of the buyers. Even at this time, a large population takes medicine and drugs without prescribing a doctor, which in fact is a very wrong decision and can be dangerous.

Thanks to a virtually "absent" adverse drug reaction mechanism in the country, drugs like Analgin, Cisapride, Nimesulide and Piperazine, discarded worldwide due to serious side effects are among the bestsellers in India. According to a report of the World Health Organisation, there has not been a single instance of adverse drug reaction reported against any drug in the country.

The business of production of these discarded drugs is booming in India. Some of the most common ones include Nise (Dr Reddy's), Nimulid (Panacea Biotec) that are discarded for reported liver damage, while Vicks Action 500 from the stable of Procter and Gamble is discarded for increasing chances of brain hemorrhage. Anti-depressant drug Droperol (produced by Triokka) has been discarded for irregular heartbeats in patients. Anti-diarrhoeal drug Furoxone (from the house of Glaxo) was withdrawn from the market after reports of cancer in some patients, who were administered the drug.

Eleven drugs - including cisapride, furazolidone, nimesulide and phenylpropanolamine - that have been banned, withdrawn or marketed under restrictions in North America, Europe and many Asian countries, continues to be sold in India.

India's contribution to the worldwide collection of data on the side effects of different drugs is dismal. Countries like Ireland, Switzerland and Italy with a population of about 4 million, 33 million and 57 million, respectively had submitted 25, 33 and 225 adverse drug reaction on nimesulide. However, India, with over 1 billion population did not report any. Another drug Sildenafil (erectile dysfunction drug) had 18 adverse drug reactions reported from Australia but none from India.

According to a health ministry source, monitoring of adverse drug reaction is not followed in the curriculum for medical students in India and majority of doctors do not maintain records on patients. Assessing adverse drug reaction is not an easy task and in a developed country like the US not more than 10% of the side effects are recorded.

"Regulations in India and US vary. In the US, drugs are not banned; they are withdrawn from the market. When a certain drug is found to have side affects, Indian regulatory authorities should also withdraw it from the market. Unfortunately that does not happen".

Whenever a drug is banned by the Drug Controller of India, it should stop being available in the market. But there are times when a drug is banned yet continues to be sold for a few months till stock lasts. "There is a lot grey zone in the field".

Drugs continue to be available over the counter because doctors keep prescribing it. "Till the time the drugs are not banned by regulatory authorities, no doctor can be blamed for prescribing it and as long as doctors keep prescribing, chemists will keep selling these drugs".

Many doctors, experts say, are unaware of the researches being conducted worldwide. "There have been campaigns against various drugs. Noted doctors keep themselves informed of the harmful side-effects of these drugs and do not prescribe them".

Many people have the opinion that "The problem is two-sided. The demand is still there for these drugs and that is why they are supplied. Doctors and patients who are used to prescribing and using

the drug should realize that there are better and safe alternatives".

Dangerous Drugs that have been globally discarded but are available in Indian markets include:

 

Analgin

It is a painkiller

Reason for ban: Bone marrow depression

Brand name: Novalgin

 

Cisapride

For acidity, constipation

Reason for ban: Irregular heartbeat

Brand name: Ciza, Syspride

 

Droperidol

Anti-depressant

Reason for ban: Irregular heartbeat

Brand name: Droperol

 

Furazolidone

Anti-diarrhoeal

Reason for ban: Cancer

Brand name: Furoxone, Lomofen

 

Nimesulide

Painkiller, fever

Reason for ban: Liver failure

Brand name: Nise, Nimulid

 

Nitrofurazone

Anti-bacterial cream

Reason for ban: Cancer

Brand name: Furacin

 

Phenolphthalein

Laxative

Reason for ban: Cancer

Brand name: Agarol

 

Pheylpropanolamine

Cold and cough

Reason for ban: stroke

Brand name: D'cold, Vicks Action - 500

 

Oxyphenbutazone

Non-steroidal anti-inflammatory drug

Reason for ban: Bone marrow depression

Brand name: Sioril

 

Piperazine

Anti-worms

Reason for ban: Nerve damage

Brand name: Piperazine

 

Quiniodochlor

Anti-diarrhoeal

Reason for ban: Damage to sight

Brand name: Enteroquinol

 

To ensure maximum safety and security, it is advisable to get only drugs prescribed by a medical practioner. Also, ask for the details like the name of the company that manufactures it. Always buy medicines from a recognized drug store. For more information about banned drugs, please visit the following links:

1. List of Drugs banned for Marketing in India 2. Central Drugs Standard Control Organization

LIST OF DRUGS BANNED FOR MARKETING IN INDIA

 

The Government of India vide notifications published in the Gazette of India vide G.S.R. No. 578 (E) dated 23/07/1983 and subsequent amendments, made under Section 26 A of Drugs and Cosmetics Act, 1940 has prohibited the manufacture, sale and distribution of the following categories of fixed dose combinations which do not have any therapeutic justification or are likely to involve risk to human beings:

G.S.R. No. 578 (E) dt 23-07-19831. Amidopyrine.2. Fixed dose combinations of vitamins with anti-inflammatory agents and tranquilizers.3. Fixed dose combinations of Atropine and Analgesic and Antipyretics.4. Fixed dose combinations of Strychnine and Caffeine in tonics.5. Fixed dose combinations of Yohimbine and Strychnine with Testosterone and Vitamins.6. Fixed dose combinations of Iron with Strychnine, Arsenic and Yohimbine.7. Fixed dose combinations of Sodium Bromide/chloral hydrate with other drugs.8. Phenacetin.9. Fixed dose combinations of antihistaminic with anti-diarrhoeals.10. Fixed dose combinations of Penicillin with Sulphonamides.11. Fixed dose combinations of Vitamins with Analgesics.12. Fixed dose combinations of Tetracycline with Vitamin C. 

G.S.R. No. 793 (E) dt 13-12-199513. Fixed dose combinations of Hydroxyquinoline group of drugs with any other drug except for preparations meant for external use only.

G.S.R. No. 1057 (E) dt 03-11-198814. Fixed dose combinations of Corticosteroid with any other drug for internal use except for preparations meant for meter dose inhalers and dry powder inhalers.[Substituted vide GSR 738 (E) dated 9.10.2009] 15. Fixed dose combinations of Chloramphenicol with any other drug for internal use.

G.S.R. No. 304 (E) dt 07-06-199116. Fixed dose combinations of crude Ergot preparation except those containing  Ergotamine, Caffeine, analgesics, antihistamines for the treatment of migraine, headache.17. Fixed dose combinations of Vitamins with Anti TB drugs except combination of Isoniazid with Pyridoxine Hydrochloride (Vitamin B6).18. Penicillin skin/eye Ointment.

19. Tetracycline Liquid Oral preparations.20. Nialamide.21. Practolo.22. Methapyrilene, its salts.

G.S.R. No. 49 (E) dt 31-01-198423. Methaqualone.

G.S.R. No. 322 (E) dt 03-05-198424. Oxytetracycline Liquid Oral preparations.25. Demeclocycline Liquid Oral preparations.

G.S.R. No. 863 (E) dt 22-11-198526. Combination of anabolic Steroids with other drugs.27. Fixed dose combination of Oestrogen and Progestin (other than oral contraceptives) containing per tablet Estrogen content of more than 50 mcg (equivalent to Ethinyl Estradiol) and Progestin content of more than 3 mg (equivalent to Norethisterone Acetate) and all fixed dose combination injectable preparations containing synthetic Oestrogen and Progesterone. (Subs. By Noti. No. 743 (E) dt 10-08-1989)

G.S.R. No. 999 (E) dt 26-12-199028. Fixed dose combinations of Sedatives/ hypnotics/anxiolytics with analgesics-antipyretics.29. Fixed dose combinations of Pyrazinamide, other anti-tubercular drugs except combination of Pyrazinamide with Rifampicin and INH per recommended daily dose given below:       Drugs Minimum Maximum       Rifampicin 450 mg 600 mg       INH 300 mg 400 mg       Pyrazinamide 1000mg 1500 mg30. Fixed dose combination of Histamine H-2 receptor antagonists with antacids except for those combinations approved by Drugs Controller, India.31. The patent and proprietary medicines of fixed dose combinations of essential oils with alcohol having percentage higher than 20% proof except preparations given in the Indian Pharmacopoeia.32. All Pharmaceutical preparations containing Chloroform exceeding 0.5% w/w or v/v whichever is appropriate.

G.S.R. No. 69 (E) dt 11-02-199133. Fixed dose combination of Ethambutol with INH other than the following: INH Ethambutol 200 mg. 600 mg. 300 mg. 800 mg.34. Fixed dose combination containing more than one antihistamine.35. Fixed dose combination of anthelmintic with cathartic/purgative except for piperazine.36. Fixed dose combination of Salbutamol or any other bronchodilator with centrally acting anti-tussive and/or antihistamine.37. Fixed dose combination of laxatives and/or anti-spasmodic drugs in enzyme preparations.38. Fixed dose combination of Metoclopramide with systemically absorbed drugs except fixed dose combination of metoclopramide with aspirin/paracetamol

G.S.R. No. 395 (E) dt 19-05-199939. Fixed dose combination of centrally acting, antitussive with antihistamine, having atropine like activity in expectorants.40. Preparations claiming to combat cough associated with asthma containing centrally acting antitussive and/ or an antihistamine.41. Liquid oral tonic preparations containing glycerophosphates and/or other phosphates and / or central nervous system stimulant and such preparations containing alcohol more than 20% proof.42. Fixed dose combination containing Pectin and/or Kaolin with any drug which is systemically absorbed from GI tract except for combination of Pectin and/or Kaolin with drugs not systemically absorbed.

G.S.R. No. 304 (E) dt 07-06-199143. Chloral Hydrate as a drug.

G.S.R. No. 612 (E) dt 09-08-199444. Dovers Powder I.P.45. Dover's Powder Tablets I.P.

G.S.R. No. 731 (E) dt 30-09-199446. Antidiarrhoeal formulations containing Kaolin or Pectin or Attapulgite or Activated Charcoal.47. Antidiarrhoeal formulations containing Phthalyl Sulphathiazole or Sulphaguanidine or Succinyl Sulphathiazole.48. Antidiarrhoeal formulations containing Neomycin or Streptomycin or Dihydrostreptomycin including their respective salts or esters.49. Liquid Oral antidiarrhoeals or any other dosage form for pediatric use containing Diphenoxylate or Atropine or Belladona including their salts or esters or metabolites Hyoscyamine or their extracts or their alkaloids.50. Liquid Oral antidiarrhoeals or any other dosage form for pediatric use containing halogenated hydroxyquinolines.51. Fixed dose combination of antidiarrhoeals with electrolytes.

G.S.R. No. 57 (E) dt 07-02-199552. Patent and Proprietary Oral Rehydration Salts other than those conforming to the following parameters:      (a) Patent and Proprietary Oral Rehydration Salts on reconstitution to one litre shall contain:- Sodium - 50 to 90 millimoles. Total osmolarity - 240 - 290 milli osmoles. Dextrose : Sodium molar ratio - Not less than 1:1 and not more than 3:1      (b) Patent and Proprietary cereal based Oral Rehydration Salts on reconstitution to one litre shall contain :- Total osmolarity - Not more than 2900 milli osmoles. Precooked rice- Equivalent to not less than 50 gm and not more than 80 gm as total replacement of Dextrose.      (c) Patent and Proprietary Oral Rehydration Salts (ORS) may contain aminoacids in addition to Oral Rehydration Salt conforming to the parameters specified above and labeled with the indication for "Adult Choleratic Diarrhoea" only.      (d) Patent and Proprietary Oral Rehydration Salts shall not contain Mono or Polysaccharides or saccharin sweetening agent.

G.S.R. No. 633 (E) dt 30-09-1995, GSR No. 123 (E) dt 11-03-1996 and GSR No. 230 (E) dt 04-06-199653. Fixed dose combination of Oxyphenbutazone or Phenylbutazone with any other drug.

G.S.R. No. 405 (E) dt 03-06-199654. Fixed dose combination of Analgin with any other drug.

    Clarification: Fixed dose combination of Analgin with any other drug other than antispasmodics were banned by the Government of India vide G.S.R. No. 633(E), dated 13.09.1995. However, the Drug Action Forum contended before the Supreme Court that the preparations of Analgin and antispasmodics should also be banned. Dr. J.S. Bajaj, being directed by the court, submitted his report supporting these contentions.

     On 17th Dec. 1996, a learned additional Solicitor submitted that the Central Government has decided that all State/U.T. Drug Licensing Authorities will be given directions by the Government under Section 33-P of the Drugs and Cosmetics Act, to suspend manufacturing licenses of all fixed dose formulations of Analgin including Analgin with Antispasmodics till further notice. Accordingly, the Government of India, under letter dated 17th Dec.1996, issued such directives. In view of the above

directives, the manufacture, sale and distribution of fixed dose combinations of Analgin and antispasmodics is prohibited.

55. Fixed dose combination of dextropropoxyphene with any other drug other than anti-spasmodics and/or non-steriodal anti-inflammatory drugs (NSAIDS).56. Fixed dose combination of a drug, standards of which are prescribed in the Second Schedule to the said Act with an Ayurvedic, Siddha or Unani drug.

G.S.R. No. 93 (E) dt 25-02-199757. Parenteral preparations containing fixed dose combination of streptomycin with penicillins with effect from 01-01-1998.

G.S.R. No. 499 (E) dt 14-08-199858. Mepacrine Hydrochloride (Quinacrine and its salts) in any dosage form for use for female sterilization or contraception.59. Fenfluramine and Dexfenfluramine.60. Fixed dose combination of haemoglobin in any form (natural or synthetic).61. Fixed dose combination of Pancreatin and Pancrelipase containing amylase, protease, and lipase with any other enzyme.

(Both 59 & 60 added by G.S.R. 590 (E) dt. 17-8-1999.Sr. No. 59 & 60 omitted by G.S.R. 704(E) dt. 20-10-1999.)G.S.R. No. 702 (E) dt 20-10-1999

62. Fixed dose combination of Vitamin B1, Vitamin B6 and Vitamin B12 for human use with effect from 01-01-2001

G.S.R. No. 814 (E) dt 16-12-1999 (w.e.f. 01-09-2000)63. Fixed dose combination of haemoglobin in any form (natural or synthetic).64. Fixed dose combination of Pancreatin and Pancrelipase containing amylase, protease and lipase with any other enzyme.

G.S.R. No. 169 (E) dt 12-03-200165. Fixed dose combination of Diazepam and Diphenhydramine Hydrochloride.

G.S.R. No. 170 (E) dt 12-03-2001 (with effect from 01-01-2002)66. Fixed dose combination of Nitrofurantoin and trimethoprim.67. Fixed dose combination of Phenobarbitone with any anti-asthmatic drug.68. Fixed dose combination of Phenobarbitone with Hyoscin and/or Hyoscyamine.69. Fixed dose combination of Phenobarbitone with Ergotamine and/or Belladona.70. Fixed dose combination of Haloperidol with any anti-cholinergic agent including Propantheline Bromide.71. Fixed dose combination of Nalidixic Acid with any anti-amoebic including Metronidazole.72. Fixed dose combination of Loperamide Hydrochloride with Furazolidone.73. Fixed dose combination of Cyproheptadine with Lysine or Peptone.

G.S.R 603 (E) dt 13-08-2001 (with effect from 01-09-2002)74. Fixed dose combination of Metoclopramide with other drugs except combination of Metoclopramide with Aspirin/ Paracetamol with effect from 1st September, 2002.

G.S.R. No. 732 (E) dt 29-10.2002, Amended vide GSR 191(E) dt 05-03-2003 (with effect from 01-04-2003)75. Astemizole

     Terfinadine

G.S.R 100 (E) dt 11-02-2003 (with effect from11-02-2003)76. Fixed dose combination of Rifampicin, Isoniazid and Pyrazinamide, except those which provide daily adult dose given below: - 

             Drugs              Minimum             Maximum                                                Rifampicin       450  mg                600 mg                                                    Isoniazid         300  mg               400  mg                                                    Pyrazinamide 1000 mg              1500  mg”

G.S.R. No. 780 (E) dt 01-10-2003 (with effect from 01-10-2003)77. Phenformin for human use.

G.S.R. No. 810 (E) dt 13-12-2004 (with effect from 13-12-2004)78. Rofecoxib and its formulations for human use.

G.S.R. No. 510 (E) dt 25-7-2005 (with effect from 25-7-2005)79. Valdecoxib and its formulations for human use.

G.S.R. No. 499 (E) dt 4/5-7-2008 (with effect from 4/5-7-2008)80. Diclofenac and its formulations for animal use.

In addition to the above-mentioned drugs, manufacture and sale of all Cosmetics and all Ayurvedic Drugs licensed as toothpaste, tooth powders containing tobacco have been prohibited under G.S.R. 443 (E) and 444(E) dated 30.4.92

1. Amidopyrine.

  2. Fixed dose combinations of vitamins with anti-inflammatory agents and tranquilizers.

  3. Fixed dose combinations of Atropine in Analgesics and Antipyretics.

4. Fixed dose combinations of Strychnine and Caffeine in tonics.

5.Fixed dose combinations of Yohimbine and Strychnine with Testosterone and  Vitamins.

 6. Fixed dose combinations of Iron with Strychnine, Arsenic and Yohimbine.

7. Fixed dose combinations of Sodium Bromide/chloral hydrate with other drugs.

8. Phenacetin.

9. Fixed dose combinations of antihistaminic with anti-diarrhoeals.

10. Fixed dose combinations of Penicillin with Sulphonamides.

11. Fixed dose combinations of Vitamins with Analgesics.

    B      12.Fixed dose combinations of  any other Tetracycline with Vitamin C.  

    E     13.Fixed dose combinations of Hydroxyquinoline group of drugs with any other drug   except for preparations meant for external use. 

  ccc     14. Fixed dose combinations of Corticosteroids with any other drug for internal use.

  ccc     15. Fixed dose combinations of Chloramphenicol with any other drug for internal use.

16.Fixed dose combinations of crude Ergot preparations except those containing Ergotamine, Caffeine, analgesics, antihistamines for the treatment of migraine, headaches. 

17.Fixed dose combinations of Vitamins with Anti TB drugs except combination of Isoniazid with Pyridoxine Hydrochloride (Vitamin B6).

18. Penicillin skin/eye Ointment.

19. Tetracycline Liquid Oral preparations.

20. Nialamide.

21. Practolol.

22. Methapyrilene, its salts.

c    23. Methaqualone.

&   24. Oxytetracycline Liquid Oral preparations.

&  25. Demeclocycline Liquid Oral preparations.

T    26. Combination of anabolic Steroids with other drugs.

cc  27.Fixed dose combination of Oestrogen and Progestin (other than oral contraceptive) containing per tablet estrogen content of more than 50 mcg (equivalent to Ethinyl Estradiol) and progestin content of more than 3 mg (equivalent toNorethisterone Acetate) and all fixed dose combination injectable preparations containing synthetic Oestrogen and Progesterone. (Subs. By Noti. No. 743 (E) dt 10-08-1989)

*    28.Fixed dose combination of Sedatives/ hypnotics/anxiolytics with   analgesics-antipyretics. 

J*    29.Fixed dose combination of Rifampicin, isoniazid and Pyrazinamide, except those which provide daily adult dose given below:

Drugs Minimum Maximum

Rifampicin                      450 mg                   600 mg

Isoniazid 300 mg 400 mg

Pyrazinamide                  1000mg                  1500 mg

*   30. Fixed dose combination of Histamine H-2 receptor antagonists with antacids except for those combinations approved by Drugs Controller, India.

*   31.The patent and proprietary medicines of fixed dose combinations of essential oils with alcohol having percentage higher than 20% proof except preparations given in the Indian Pharmacopoeia.

*   32. All Pharmaceutical preparations containing Chloroform exceeding 0.5% w/w or v/v   whichever is appropriate.

** 33.Fixed dose combination of Ethambutol with INH other than the following: INH   Ethambutol 200 mg. 600 mg. 300 mg. 800 mg.

     ** 34. Fixed dose combination containing more than one antihistamine.

   B** 35.Fixed dose combination of any anthelmintic with cathartic/purgative except for           piperazine/Santonim.

   J **36. Fixed dose combination of Salbutamol or any other drug having primarily bronchodilatory activity with centrally acting anti-tussive and/or antihistamine.

    **  37.Fixed dose combination of laxatives and/or anti-spasmodic drugs in enzyme preparations.

  G** 38.Fixed dose combination of Metoclopramide with systemically absorbed drugs except fixed dose combination of metoclopramide with aspirin/paracetamol

    ** 39.Fixed dose combination of centrally acting, antitussive with antihistamine, having high atropine like activity in expectorants.

    ** 40.Preparations claiming to combat cough associated with asthma containing centrally acting antitussive and/ or an antihistamine.

    ** 41.Liquid oral tonic preparations containing glycerophosphates and/or other phosphates and / or central nervous system stimulant and such preparations containing alcohol more than 20% proof.

    ** 42.Fixed dose combination containing Pectin and/or Kaolin with any drug which is systemically absorbed from GI tract except for combinations of Pectin and/or Kaolin with drugs not systemically absorbed.

  *** 43. Chloral Hydrate as a drug.

    b   44. Dovers Powder I.P.

    b   45. Dover’s Powder Tablets I.P.

    A   46.Antidiarrhoeal formulations containing Kaolin or Pectin or Attapulgite or Activated Charcoal.

    A 47.Antidiarrhoeal formulations containing Phthalyl Sulphathiazole or Sulphaguanidine or Succinyl Sulphathiazole.

    A  48.Antidiarrhoeal formulations containing Neomycin or Streptomycin or Dihydrostreptomycin  including their respective salts or esters.

    A  49.Liquid Oral antidiarrhoeals or any other dosage form for pediatric use containing Diphenoxylate Lorloperamide or Atropine or Belladona including their salts or esters or metabolites Hyoscyamine or their extracts or their alkaloids.

    A  50.Liquid Oral antidiarrhoeals or any other dosage form for pediatric use containing halogenated hydroxyquinolines.

    A  51. Fixed dose combination of antidiarrhoeals with electrolytes.

    C  52. Patent and Proprietary Oral Rehydration Salts other than those conforming to the  

    D  53. Fixed dose combination of Oxyphenbutazone or Phenylbutazone with any other drug. 

   H.D54. Fixed dose combination of Analgin with any other drug.

     D 55. Fixed dose combination of dextropropoxyphene with any other drug other than anti-spasmodics and/or non-steriodal anti-inflammatory drugs (NSAIDS).

     D 56. Fixed dose combination of a drug, standards of which are prescribed in the Second Schedule to the said Act with an Ayurvedic, Siddha or Unani drug.

     F 57. Mepacrine Hydrochloride (Quinacrine and its salts) in any dosage form for use for female sterilization or contraception.

     F  58. Fenfluramine and Dexfenfluramine.

     I  59. Fixed dose combination of Diazepam and Diphenhydramine Hydrochloride . 

     K  60. Rimonabant.

LIST OF GAZETTE NOTIFICATION PUBLISHED

    The Principal Notification GSR 578 (E) dt.23.7.83.

c    Added b GSR 4(E) dated 31.01.1984

&   Added b GSR 322(E) dated 03.05.1984\

T   Amended by GSR 863(E) dated 22.11.1985

cc   Amended by GSR 743(E) dated 10.08.1989

ccc Amended by GSR 1057(E) dated 03.11.1988

*    Added by GSR 999(E) dated 26.12.1990

         * Added by GSR 69(E) dated 11.02.1991

       xxx    Added by GSR 304(E) dated 7.06.1990

     @   Added by GSR 444(E) dated 7.06.1992

      b   Added by GSR 111(E) dated 22.02.1994

      A   Added by GSR 731(E) dated 30.09.1994

      B   Added by GSR 848(E) dated 7.12.1994

      C   Added by GSR 57(E) dated 7.02.1995

      D   Added by GSR 633(E) dated 13.09.1995

      E   Added by GSR 793(E) dated 13.03.1995

Added by GSR 93(E) dated 25.05.1997

      F   Added by GSR 499(E) dated 14.08.1998

      G   Added by GSR 394(E) dated 19.05.1999

      H   Added by GSR 405(E) dated 3.06.1999

      I    Added by GSR 169(E) dated 12.03.2001 

      J   Added by GSR 290(E) dated 16.04.2008

       K   Added by GSR 885(E) dated 11.12.2009

LIST OF DRUGS PROHIBITED FOR IMPORT 

           1. Nialamide

        2. Practolol

        3. Amidopyrine

        4. Phenacetin

        5. Methapyrilene and its salts

   a   6. Methaqualone

   b   7. Chloral Hydrate as a drug

   c   8. Mepacrine Hydrochloride ( Quinacrine and its Salts) in any dosage form for use for female sterilization or contraception.

        9. Fenfluramine and Dexfenfluramine]

   d   10. Rimonabant

LIST OF GAZETTE NOTIFICATION PUBLISHED

    a  Added by GSR 48(E) dated 31.1.1984

    b  Added by GSR 303(E) dated 7.6.1991

    c  Added by GSR 498(E) dated 14.8.1998

    d Added by GSR 884(E) dated 11.12.2009

DRUGS PROHIBITED FOR MANUFACTURE , SALE  AND DISTRIBUTION FROM SUBSEQUENT DATE 

Drugs Formulation Effective date Notification  

 

1.Cosmetics Licensed as toothpaste/tooth           With immediate         GSR 444(E) 

   powder containing tobacco.                             effect                       dt.30.4.92 

2.Parenteal Preparations fixed dose                     Jan 1,1998               GSR 93(E)

   combination of streptomycin with                                                      dt.25.2.97

   Pencillin 

3.Fixed dose combination of Vitamin B1,               Jan 1,2001               GSR 702(E)

   Vitamin B6 and Vitamin B12 for                                                        dt.14.10.99

   human use  

4.Fixed dose combination of haemoglobin             Sep 1,2000               GSR 814(E)

 in any form (natural or synthetic).                                                    dt.16.12.99 

5.Fixed dose combination of Pancreatin or            Sept. 1,2000             GSR 814(E)

  Pancrelipase containing amylase, protease                                          dt.16.12.99 

  and lipase with any other enzyme. 

6. Fixed dose combination of Nitrofurantoin          Jan 1,2002                GSR 170(E)

    and trimethoprim.                                                                          dt.12.3.01 

7.Fixed dose combination of Phenobarbitone         Jan 1,2002                GRS 170(E)  

 with any anti-asthmatic drugs.                                                           dt.12.3.01 

8.Fixed dose combination of Phenobarbitone         Jan 1,2002                GSR 170(E)

   with Hyoscin and/or Hyoscyamine                                                     dt.12.3.01 

9.Fixed dose combination of Phenobarbitone         Jan 1,2002                GSR 170(E)

 with Ergotamine and/or Belladona                                                     dt.12.3.01 

10.Fixed dose combination of Haloperidol              Jan 1,2002                 GSR 170(E)

     with any anti-cholinergic agent including                                          dt.12.3.01

     Propantheline Bromide. 

11.Fixed dose combination of Nalidixic Acid           Jan 1,2002                   GSR 170(E)

     with any anti-amoebic including Metronidazole.                                   dt.12.3.01  

12.Fixed dose combination of Loperamide             Jan 1,2002                  GSR 170(E)

     Hydrochloride with Furazolidone                                                      dt.12.3.01 

13.Fixed dose combination of Cyproheptadine       Jan 1,2003                  GSR 170(E)

 with Lysine or Peptone.                                                                    dt.12.3.01 

14.Astemizole                                                 Apr.1,2003                   GSR 191(E)

                                                                                                         dt.5.3.03 

15.Terfinadine                                                 Apr.1,2003                   GSR 191(E)

                                                                                                         dt.5.3.03 

16.Fenformin                                                   Oct.1,2003                   GSR 780(E)

                                                                                                      dt.1.10.03  

17.Rafecoxib                                                  Dec 13,2004                  GSR 810(E)                                                                                                      dt. 13.12.04

18.Valdecoxib                                                July 25,2005                   GSR 510(E)    and it's formulation dt. 25.07.05

19.Diclofenac and its formulations                     July 4, 2008                    GSR 499(E)

    for animal use                                                                                dt.4.07.08

Health and Fitness  

Dangers of Self MedicationA large number of people, when they fall sick, do not consult the physician. They either consult a chemist and obtain a medicine from his shelf, or may consult a neighbor who may be having some tablets left over from his previous illness, and readily spares them. Have you ever noticed

that right from popular magazine editors to your domestic servant thinks that he or she is a medical authority? If you have a fever, cold, cough, constipation or indigestion, your friends or even total strangers volunteer advice on medicines to take like expert physicians. Almost everyone you meet has an excellent remedy for whatever ails you. In short, this is what  is meant be self-medication. May be most of the times nothing untoward happens on following such advice, but it can be dangerous.

We today are a crazy pill-popping generation. It is rightly said that the desire to take medicines, is one feature that distinguishes man from animals. Recent advances in drug research have provided many synthetic medicines for the treatment of disease, leading to a drug explosion. Today over 7000 drugs and drug combinations are available. Many of them have been released for general use, and are sold directly to the public as over-the-counter (OTC) remedies. A large number of potent drugs are thus available to the individual for self-medication. There is an obvious difference between drugs and other commodities of life. The consumer has no way to judge the efficacy of a drug or its hazards, and therefore these judgments have to be made for him by physicians.

Paracelsus (1493-1541), the alchemist-physician, in the 16th century observed that all drugs are poisons. The availability of potent and dangerous drugs has increased considerably since the close of the 19th century. At the same time expanding availability of medical care, exposes a large population of people to drugs, leading to a greater number of toxic reactions. This situation is further worsened in our country by the slack implementation of Drug Control. Even certain prescription drugs are available to the lay person without the physician's advice. As people vary greatly in their sensitivity to drugs, an appropriate dose for one person can be an overdose for another. Even skilled physicians sometimes fail to  avoid such reactions. Thus, the lay person is ill-advised in subjecting himself to potentially dangerous self-medication.

Proprietary drugs which are sold over-the-counter include pain relievers, cough remedies, antiallergics, laxatives, vitamins, tonics, antacids and many others. Even dangerous drugs like  the antibiotics and the hormones can be procured, somehow or the other, without a valid prescription. This is an entirely different facet of drugging. It is encouraging to note that stricter 'drug control' is being gradually clamped country-wide.

Self-medication usually involves common drugs which are freely available. A study carried out in the United States showed that nearly 2 billion dollars per year were spent on such remedies. It is questionable whether the benefits outweigh the potential hazards. They account for poisonings, allergy, habituation, addiction, and other adverse reactions. Above all their use often delays proper treatment of the disease.

The most misused drugs are the analgesics or pain relievers. In fact, age old, ordinary aspirin is as effective, and even safer than any of the modern analgesics like fenamates, oxicams, or Cox-2 inhibitors like rofecoxib and celecoxib. A probable factor causing lavish prescribing and selling of such drugs is vigorous promotion gimmicks by pharmaceutical firms. Today it may even be difficult to obtain simple aspirin in the market. The physicians have apparently accepted the manufacturer's claims and recommend the "modern analgesics" despite their greater cost. Similarly cough remedies, antiallergics, laxatives, vitamins, tonics, and  antacids can lead to serious side effects. Even lavish use of vitamins, specially the fat-soluble (A,D,E, &K) can cause problems. I am reminded of the great English philosopher-physician Sir William Osler (1849-1919) who said, "One of the first duties of the physician is to educate the masses when not to take medicines"

Another hazard is the availability of many irrational drug combinations in the market, which expose the individual to several drugs needlessly, each of which can cause adverse effects. Very few combinations have a legitimate place in modern medicine. Yet irrational combination abound and are being used by some professionals.

Thus, to avoid or minimize the dangers of self-medication, firstly, the lay person should be educated about the dangers of indiscriminate use of drugs. Secondly, the physicians should  be more judicious in prescribing, and must insist on drugs being supplied by the chemist only on a valid prescription. Thirdly, a proper statutory "Drug Control" must be implemented, rationally restricting the availability of drugs to the public. These three measures would definitely reduce  the incidence of drug-related mishaps, and help in maintaining good health of the individual and society. 

– Dr. Frank S.K. BararFebruary 27, 2005

DCGI develops cold feet over irrational FDCsJayashree Padmini - New Delhi

The government has failed to take effective measures to curb the crowd of irrational fixed dose combinations (FDCs) in the domestic market. The assurances that DCGI will look into the data of drugs approved by the state drug authorities in the last five years and study the safety profile of such FDCs that may pose health risks, remained only a promise.

Rough estimates suggest that there would be at least 100 of such FDCs in the domestic market. The Nimesulide+Paracetamol combination brands alone have MAT of Rs 30.2 crore as per ORG February 2003 figures.

Sources close to DCGI said that the government has banned several FDCs wherein medical professionals have come forward with adverse impact information. ‘‘However, on all FDCs that are already approved by state authorities, it is not possible to revoke the license till the time we get proof for its irrationality,’’ stated the source.

However, it is clear that such FDCs do not comply with the Drugs & Cosmetics Act and state drug authorities could not give manufacturing licenses without prior marketing approval from DCGI. The source added, ‘‘States have now been strictly told not to approve such FDCs. Moreover, the ADR monitoring mechanism now started and completion of the ongoing computerization of drug control offices would contribute a big way in making the system more transparent to control such irrational practices.’’

However, after the said letter to state drug authorities on May 1, 2002, it is learnt at least

12 such combinations were given manufacturing licenses without asking for prior DCGI approval for marketing. These include Namcold of Lincoln Pharma (Nimesulide+Cetirizine+psuedoephedrine), Emusulide-Sen (Emcure) Nidegefic (VIP Pharma) both Nimesulide+Diclofenac combination and Nimpac of Sysmed (Nimesulide+Chlorzoxazone) and Nobelspas of Mankind (Nimesulide+drotaverine) among others.

Ironically, the DCGI’s office despite its stand that it cannot review the licenses given already, has banned Cipla’s FDC thus introduced, i.e., Montair Plus (Montelukast+Bambuterol). Such FDCs becomes illegal because most of these have neither submitted human clinical trial data nor obtained marketing permission from DCGI.

Under the Drugs & Cosmetics Act 1940, new drugs need to submit clinical trial data to the DCGI and get approval which was not the case in many of the existing FDCs. Drugs & Cosmetics Rules 1945- Rule 122 D states, import and manufacture of FDCs already approved as individual drugs by DCGI would require to submit information and data as prescribed by Apendix VI of Schedule Y.

According to Schedule Y Appendix VI (b), such FDCs where active ingredients are already approved/marketed individually, reports of clinical trials carried out in the country should be submitted. When ratio of ingredients in approved FDCs is to be changed also manufacturers need to submit trial data to DCGI.

Rule 122E defines new drug as one, as defined in the Act including bulk drug substance which has not been used in the country to any significant extent under the conditions prescribed or suggested in the labelling thereof and has not been recognized as effective and safe by the Licensing Authority.

Take the example of Nimesulide. Of the total Nimesulide market more than 28 per cent sales come from FDCs. The combinations are either with paracetamol or with other drugs such as diclofenac, dicyclomine, chlorzoxazone, methocarbamol, camylofin, tizanidine, etc. There are three ingredient combinations such as nimesulide-cetirizine-psuedoephedrine, and nimesulide-paracetamol-tizanidine.

These FDCs which are not recognized in major pharma markets such as US and Europe, are said to be approved in the country by state drug control authorities for manufacturing. The major brands in the Nimesulide+Paracetamole category in terms of market share as per ORG MAT February 2003 are Sumo, Nimsaid-P, Niap and Dolamide (Ranbaxy). Others include Emusulide-P (Emcure), Nimicaplus (IPCA Laboratories) and Parazolantin (Sarabhai Piramal).

The FDC concept is a market capturing strategy, point out a medical expert based in Delhi. While there are already established brands of Nise or Nimulid (Nimesulide) and Crocin or Calpol (Paracetamol) in the market, the new combination tries to eat into their markets by suggesting that such a combination is instant acting in a disease situation. Further, market positioning is that it would be available at lower price compared to purchasing both separately, pointed out the expert.

However, the claim of offering at lower price is only eye wash, figures suggest. Nise, Nimesulide 100mg 10 tablets pack costs Rs 25.74 and Crocin, Paracetamol 500mg 10 tablets pack costs Rs 7.60. Dolamide, combination of both, costs Rs 27.50. Paracetamol prices average is at Rs 225 per Kg. This means 500 mg paracetamol would cost 25 Ps. For

the combination as the manufacturer need to do tabletting, stripping, packing, printing, etc., only once such expenses would be accounted for only once and manufacturer get the advantage.

The price increase should have been only that to account for the added amount of paracetamol, but a hike of Rs 1.76 shakes the claim that combinations are economical. The highest concern is on the safety profile of such FDCs where the rationality of the combination is not proved by the manufacturer, explains medical experts citing the example of paracetamol+nimesulide combination where both the drugs with liver toxicity when added could lead to doubling the adverse impact.

Moreover, dosing interval cannot match when it is combination. Paracetamol is advised to take twice a day 500 mg each and for nimesulide 100 mg dosage is four to six times a day. Further, there have been no study on the adverse interaction in the tablet between the active ingredients and when in stomach or in blood.

Glibenclamide+Metformin combination for diabetics is another hot spot manufacturers jumps in to cash in on at the cost of health risk to patients. Another dangerous FDC segment where usage could give way to development of drug resistant bacteria is combination of Quinolones such as Ciprofloxacin, Ofloxacin & Norfloxacin with Imidazoles like Tinidazole & Metronidazole.

Does Glimy MP help control high sugar levels?

Thursday, 13 March 2008

Answered by: Dr. Chandra M. GulhatiEditor,MIMS,New Delhi

Q. How does Glimy MP function in controlling diabetes? I am 65 years old and weigh 68 kg. My height is 5.5 feet.A.  Glimy MP is a combination of three medicines: glimepiride, metformin and pioglitazone. Such an irrational combination is not permitted to be sold in any advanced country. The side effects of pioglitazone alone may include the following: cardiovascular disorders, heart failure, liver & biliary disorders, abnormal SGPT/SGOT/CPK levels, visual disturbance, upper respiratory tract infection, weight gain, hypoaesthesia, sinusitis, pharyngitis, myalgia, dyspnoea, new or worsening of diabetic macular oedema and bladder cancer. When taken with metformin the additional side effects may include the following: anaemia, oedema, weight gain, headache, haematuria (blood in urine), visual disturbance, joint pain (arthralgia) and impotence. When taken with glimepiride the additional side effects may include: Weight gain, dizziness, flatulence and oedema. Thus if all the three medicines are taken then side effects are more than its benefits. Hence pioglitazone alone is given particularly in obese patients only when metformin cannot be given or is not tolerated. Pioglitazone in combination with metformin is given when metformin

alone is not adequate to control blood sugar. Pioglitazone in combination with glimepiride is given when the patient cannot tolerate metformin. However the three drugs i.e. glimepiride, metformin and pioglitazone are never given together. I may add here that the innovator of pioglitazone, Takeda Pharmaceuticals, has issued additional guidelines and warnings on the use of the drug in diabetes. Briefly it states that: (a) Pioglitazone is not for all diabetics. (b) It can cause fluid retention that can precipitate or worsen congestive heart failure (CHF). There is 39 per cent increase in the risk of CHF in patients taking pioglitazone compared to those who are not on this medicine and (c) LFTs (liver function tests) must be done before starting pioglitazone and periodically thereafter. Patients must be instructed to consult their doctors if there is rapid weight gain, shortness of breath, nausea, vomiting, abdominal pain, tiredness, loss of appetite, dark urine or yellowing of skin.

Read more at:http://doctor.ndtv.com/faq/ndtv/fid/12734/Does_Glimy_MP_help_control_high_sugar_levels.html?cp

Which drugs are safe for diabetes?

Wednesday, 20 October 2004

Answered by: Chandra M. GulhatiEditor,MIMS,New Delhi

Q. I am 55 years old and I am suffering from diabetes for the past 6 years. I am 5 feet 11 inches tall and I used to weigh 80 kg 6 years back. I was prescribed Glucored plain one tablet to be taken before breakfast and one before dinner. The sugar level was 120 (fasting) and 160 (post meal). After 4 years my sugar levels shot up to 150 (fasting) and 210 (post meal). The doctor prescribed Glypride 2 mg two tablets (before break fast and dinner) and one piozone M 15 after lunch. I have taken it upto last month, but it has not control on my sugar levels properly and my weight has reduced to 75 kg. I started taking glucored forte one before breakfast and one before dinner. Now my sugar level is 120 (fasting) and 160 (post meal). Some doctors say that Glucored is an old medicine and it is not prescribed nowadays. Should I continue with glucored forte?A.  One of the serious problems facing the people of India is the marketing of totally illegal and irrational combinations of medicines in one tablet. Nowhere in the western world does one find such combinations called fixed-dose combinations (FDC). In diabetes, it is necessary to titrate (increase or decrease) the quantity of various medicines depending on response. This can not be done in FDCs. That is why they are irrational. For example, Glycored is a combination of two medicines: glibenclamide 2.5 mg and metformin 400 mg. Glycored Forte contains 5mg of glibenclamide (i.e. double of plain Glycored) but only 25% more metformin (i.e. 500 mg instead of 400 mg of plain Glycored). Suppose you require 2.5 mg of glibenclamide twice daily and 500 mg of metformin twice daily - this cannot be done with an FDC. Besides, there are scientific trials to see how two medicines when combined in one tablet may be interacting with each other. It is difficult to understand the reasons behind your being transferred to Glypride (glimepiride) and Piozone (pioglitazone), a reserve medicine to be used only when all other conventional

medicines have failed. It would have been more logical to titrate the dose of glibenclamide and metformin - two tried and tested medicines. Now you are again taking glibenclamide 5 mg twice daily and metformin 500 mg twice daily. It would be better to take them independently i.e. glibenclamide (Daonil 5 mg) morning evening and metformin (Glyciphage 500 mg) morning evening. In case at some stage in future your blood sugar goes out of control, you can at least increase Daonil 2.5 mg or 5 mg to three times daily and Glyciphage 500 mg 3 times daily or to shift to Glyciphage 850 mg twice or thrice daily by carefully titrating the dose. This is best done by the patient himself. Please also keep in mind that in the field of medicines, well tried and tested conventional drugs are safer than newer ones with which we have very little experience.

Read more at: http://doctor.ndtv.com/faq.aspx?fid=5380&cp

Date:11/07/2007 URL: http://www.thehindubusinessline.com/2007/07/11/stories/2007071152760300.htm

Dr Reddy’s launches new diabetes drugs

Our Bureau

Hyderabad, July 10 The Hyderabad-based Dr Reddy’s Laboratories launched Glimy MP1 and Glimy MP2 for management of Type II diabetes.

Glimy MP, a triple drug combination (Glimepiride, Metformin and Pioglitazone) was an extension of the existing products of Dr Reddy’s, used in the management of Type 2 diabetes. It was a one step approach to intensive glycemic control, according to a release issued here.

The drug is available in dosages of 1mg (Glimy MP1) and 2mg (Glimy MP2), in sizes of 10 tabs /strip and 10 strips/pack.

Combination

The triple drug combination oral hypoglycemic agents market is about Rs 62 crore in size and has grown by 176 per cent in the last one year.

Diabetes is a metabolic disease with three anomalies i.e. reduced insulin secretion, decreased insulin sensitivity & increased hepatic glucose production.

Glimepiride would work by increasing the insulin secretion, Metformin acts by decreasing the hepatic glucose output while Pioglitazone would act by increasing the insulin sensitivity.

Thus, the triple combination would address all the three anomalies in diabetes, the release added.

Hay fever drug to be banned by the FDA

The United States Food and Drug Administration (FDA) has announced that it plans to ban terfenadine, a popular antihistamine which has been on the market since 1985.

In 1992, however, it became known that terfenadine may cause prolongation of the QT interval and trigger fatal ventricular arrhythmias. This side effect is seen when the drug is taken concomitantly with the antibiotics erythromycin and clarithromycin and with the antifungals ketoconazole …