Irrational Combinations and Banned Drugs

Pharmabizz.com
Wednesday, 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. Amidopyrine
2. Phenacetin
3. Sulphanilamide
4. Practolol
5. Methapyrilence and its salts
6. Penicillin skin/ eye ointment
7. Tetracycline liquid
8. Oxytetracycline liquid oral preparation
9. Demeclocycline liquid oral preparation
10. Methaqualone
11. FDC of chloramiphericol with other drugs for internal use
12. FDC of Ergot with any drugs
13. FDC of Vitamins with anti-inflammatory agents and tranquilisers
14. FDC of Atropine with analgesics and antipyretics
15. FDC of Yohimbine and strychnine with Testosterone and vitamins.
16. FDC of iron with Strychnine, Arsenic and Yohimbine.
17. Chloral hydrate
18. 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 Sulfonamides
22. FDC of vitamins with analgesics
23. 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 use
27. 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 NSAID
52. 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/or
Hyoscyamine.
61. Fixed dose combination of Phenobarbitone with Ergotamine and/or
Belladona.
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 Industry
By - 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).
12
Drug control issues: Indian scenario
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. AmitavaSen. 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.com
Wednesday, 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 point
Chandler 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.
• Other Sections▼

REFERENCES
1. 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 Avoid

If you're mixing supplements and prescription pills, you may be getting a risky
blend of medications
By DEBORAH KOTZ
Posted: December 23, 2008
Note 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 undergraduates

Author: Gautam CS, Aditya S
Department 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 menace
P. A. FRANCIS
Even 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 Combinations

Author: Christina Dye
Publisher: Do It Now Foundation
Publication
March 2010
Date:
Catalog
121
Number:

..The Simple Facts

There are hundreds of studies, crammed with millions of words, examining the subject of alcohol-drug
interactions
from 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
Severe reactions to even small amounts:
Anti-Alcohol Antabuse®
headache, nausea, convulsions, coma, death.
Penicillin,
Antibiotics Reduces the drugs' therapeutic effectiveness.
Cyantin®
Increased central nervous system (CNS)
Elavil®,
depression and blood pressure changes.
Prozac®,
Antidepressants Combination use of alcohol with MAO inhibitors
Tofranil®,
can trigger massive increase in blood pressure,
Nardil®
resulting in brain hemorrhage and death.
Allerest®, Drowsiness and CNS depression. Impairs
Antihistamines
Dristan® driving ability.
Can intensify alcohol's effects. Irritates stomach
Anacin®,
Aspirin lining. May cause gastrointestinal pain,
Excedrin®
bleeding.
Valium®, Dangerous CNS depression, loss of
Depressants Ativan®, coordination, coma. High risk of overdose and
Xanax® death.
heroin, codeine, Serious CNS depression. Possible respiratory
Narcotics
Darvon® arrest and death.
Masks the depressant action of alcohol. May
amphetamine,
Stimulants increase both blood pressure and physiological
cocaine
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.com
Wednesday, 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_Cip
rofloxacin_and_Voltaron_used_for.html?cp

EDITORIAL
Irrational fixed-dose drug combinations: a sordid story of profits before patients
C 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 23-07-1983

1. 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 13-12-1995

13. 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 03-11-1988

14. 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 07-06-1991

16. 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 31-01-1984
23. Methaqualone.

G.S.R. No. 322 (E) dt 03-05-1984

24. Oxytetracycline Liquid Oral preparations.
25. Demeclocycline Liquid Oral preparations.

G.S.R. No. 863 (E) dt 22-11-1985

26. 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 26-12-1990

28. 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 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.

G.S.R. No. 69 (E) dt 11-02-1991

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.
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 19-05-1999

39. 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 07-06-1991

43. Chloral Hydrate as a drug.

G.S.R. No. 612 (E) dt 09-08-1994

44. Dovers Powder I.P.
45. Dover's Powder Tablets I.P.

G.S.R. No. 731 (E) dt 30-09-1994

46. 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 07-02-1995

52. 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-
1996
53. Fixed dose combination of Oxyphenbutazone or Phenylbutazone with any other drug.

G.S.R. No. 405 (E) dt 03-06-1996

54. 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 25-02-1997

57. Parenteral preparations containing fixed dose combination of streptomycin with penicillins with
effect from 01-01-1998.

G.S.R. No. 499 (E) dt 14-08-1998

58. 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 12-03-2001

65. 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 Medication

A 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. Barar
February 27, 2005

DCGI develops cold feet over irrational FDCs

Jayashree 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. Gulhati

Editor,
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.

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ontrol_high_sugar_levels.html?cp

Which drugs are safe for diabetes?

Wednesday, 20 October 2004

Answered by: Chandra M. Gulhati

Editor,
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.
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Date:11/07/2007 URL:
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300.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 …