(LOCOST) Low Cost Standard Therapeutics

Why Some Leading Drugs in the Indian
MarketShould Not Be Sold - But Are Still Sold

1) Fixed Dose Combinations (FDCs) of Antibiotics and or Antimicrobials

a) FDCs of Ampicillin and Cloxacillin

Brand name examples: Ampilox (Biochem); Bacilox (Alembic), Baxin (Lyka) and other such combinations in capsules, kidtabs, dry syrups, injections.

(i) Both combinations belong to same class namely penicillins acting at the same site by same mechanism offering no synergism.

(ii) Claims like cloxacillin binds to penicillinase and makes it inactive are false.

(iii) No broader spectrum of action as claimed.

(iv) Fixed ratio of drugs does not allow flexibility of changing one or other antibiotic.

Recommendations: Ban all the formulations of ampicillin with cloxacillin in all types of formulations. Concurrently they could be used in appropriate doses where necessary.

b) FDCs of Amoxicillin and Cloxacillin

Brand name examples: Hipenox caps (Cadila); Megamox-500 caps (Max);

Novaclox (Cipla) caps, tabs, injections; Tresmox caps (Sarabhai); Tormoxin plus and Twiciclox (Torrent) and other such.

All above arguments for ampicillin and cloxacillin combinations hold in this case also, in addition to the following: dosing pattern of both these antibiotics is different as mentioned in standard medical textbooks: amoxicillin is recommended three times a day whereas cloxacillin is recommended four times a day, thus creating a discrepancy in dosing time schedules.

Recommendations: As above for FDCs of ampicillin and cloxacillin: to be weeded out and can be used concurrently if necessary.

Brand Name Examples: Dinite (Searle) tabs, suspension; Entamizole (Boots) tabs, syrup; Flagyl-DF (Rhone-Poulenc) tabs; Metrogyl compound (Unique) tabs; Qugyl (Searle) tabs, suspension; Cyloxanid (Biddle-Sawyer) tabs; Wotinex (Wockhardt) tabs; Zoa Forte (Tata- Pharma) tabs and such others.

(i) Metronidazole and tinidazole are tissue amoebicides whereas diloxanide furoate and DHQ are luminal amoebicides.

(ii) The standard treatment of invasive amoebiasis is tab. metronidazole (35 to 50 mg/kg/day in the three divided doses) for 7-10 days followed by diloxanide furoate 500 mg three times a day for further 10 days.

(iii) According to Goodman and Gillman (1990) for asymptomatic and non-invasive intestinal amoebiasis, only diloxanide furoate is sufficient. In such patients these combinations will lead to unnecessary intake of metronidazole/tinidazole. In case of invasive intestinal and systemic amoebiasis, including amoebic diseases, metronidazole/tinidazole is given followed by diloxanide furoate (Goodman-Gillman, p.955).

(iv) According to Laurence D.R (Clinical Pharmacology, 1992) treatment with tissue amoebiasis should always be followed by a course of luminal amoebicide to eradicate the source of the infection (p.207).

(v) The combination is recommended nowhere.

Brand Name Examples:

Flagyl F (Rhone Poulenc) tabs, suspension; Fumedil-DS (Ethnor) caps; Kaltin-MF(Abbott) suspension; Metrogyl-F (Unique) tabs, suspension; Tini-F syrup (Kopran) and such other products.

(i) Metronidazole is primarily an antiamoebic whereas furazolidone is an antibacterial effective against colonic gram negative bacteria. Furazolidone is nowhere mentioned for use in the latest editions of Goodman Gillman (1990) and Clinical Pharmacology by D.R. Laurence (1992). They are perhaps replaced by safer and more effective agents.

(ii) All diarrhoeas/dysenteries are not polymicrobial in origin - not always due to concurrent infection by E.histolytica and colonic pathogenic bacteria. Thus a person suffering from amoebiasis is condemned to take furazolidone and a patient suffering from bacterial dysentery has to take metronidazole/tinidazole unnecessarily. This increases cost of therapy and chances of ADR.

(iii) Most diarrhoeal diseases do not need treatment with antibiotics/antibacterials. Many of them are self-limiting and need only supportive therapy like fluids and electrolytes with ORS.

Recommendations: Ban all formulations containing metronidazole/tinidazole and furazolidone combinations. They may be separately formulated and marketed in appropriate conditions.

2. FDCs of Analgesics with Analgesics/Antiinflammatory drugs

FDCs of Ibuprofen/Ketoprofen/Diclofenac with Paracetamol/Analgin

Brand Name Examples: Combiflam (Roussel) tabs and suspension; Ibugesic Plus (Cipla) tabs, susp.; Lederflam Plus (Lederle) tabs; Magadol (Alembic) tabs, suspension.; Tribusynth (Astra-IDL) tabs; Zupar (Allenburys) caps, tabs, syrup; Ketonal-D (PCI); Redufin-A (Unique); Cofenac (Protec) tabs; Diclogesic (Torrent) tabs; Diclofam Plus (Max) tabs; Fenaside-P (Nicholas) tabs; and such others.

i) i) Ingredients of all these combinations, mainly paracetamol, analgin, ibuprofen, diclofenac, etc., belong to a single category of drugs, i.e., Non-Steroidal Inflammatory Drugs (NSAIDS). Paracetamol and analgin have chiefly analgesic and antipyretic actions. Ibuprofen and diclofenac have mainly anti-inflammatory action in addition to having analgesic and antipyretic effects. All these effects are produced by inhibition of synthesis of prostaglandins. Since the mechanism of action is same, there is no synergism. More over anti-inflammatory action leads to pain relief.

(ii) NSAID combinations are known to cause direct damage to kidney (Clinical Pharmacology, Laurence, 1992, p.469.) Although nephropathy is uncommonly associated with the long-term use of individual aspirin-like drugs, the abuse of analgesic mixtures has been linked to the development of renal injury including papillary necrosis and chronic interstitial nephritis (Goodman-Gillman, 1990, p.643).

Recommendations: All such combinations should be banned. Individual ingredients, except analgin, however may be marketed for use either singly or concurrently in appropriate doses in suitable conditions.

3) Iron Preparations

a) Haemoglobin containing iron preparations
Brand Name Examples: Bio-syn (Gufic) liquid; Dexorange Plus (Franco-Indian) caps and syrup; Globac (Alidac) caps and liquid; Haem Up (Cadila) liquid and gems; Hb-Rich (Merind) liquid; Probofex with Haemoglobin (Wockhardt) syrup; Reditone Plus (Blue Cross) liquid;

(i) The source of haemoglobin is blood of animals killed in slaughter houses. This could be dangerous for human use for the fear of causing allergic reactions (foreign proteins), transmission of infections (zoonosis, because blood is a rich medium for bacterial growth), etc.

(ii) Haemoglobin per se is a poor source of elemental iron absorbed by the body. More than half a bottle of any of above preparations will be required for appropriate response in anaemic conditions

(iii) Because of lack of this knowledge on part of patients, and even doctors, it will result into subtherapeutic use and inadequate treatment.

(iv) A six-month course with such preparations will cost approx. Rs.3,650/- as against Rs.55/- (approx.) of treatment with nearly rational preparations of iron-folic acid (Macrofolin-Iron of Glaxo) available in the market.

(v) No standard textbooks of medical sciences or medical journals mention the use of haemoglobin as a drug.

For Quality, Essential, Generic Medicines
Chapter 3: Rationality of Drugs
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Appendix 2
Why Some Leading Drugs in the Indian MarketShould Not Be Sold - But Are Still Sold
1) Fixed Dose Combinations (FDCs) of Antibiotics and or Antimicrobials
a) FDCs of Ampicillin and Cloxacillin
Brand name examples: Ampilox (Biochem); Bacilox (Alembic), Baxin (Lyka) and other such combinations in capsules, kidtabs, dry syrups, injections.
Comments :
(i) Both combinations belong to same class namely penicillins acting at the same site by same mechanism offering no synergism.
(ii) Claims like cloxacillin binds to penicillinase and makes it inactive are false.
(iii) No broader spectrum of action as claimed.
(iv) Fixed ratio of drugs does not allow flexibility of changing one or other antibiotic.
Recommendations: Ban all the formulations of ampicillin with cloxacillin in all types of formulations. Concurrently they could be used in appropriate doses where necessary.
b) FDCs of Amoxicillin and Cloxacillin
Brand name examples: Hipenox caps (Cadila); Megamox-500 caps (Max);
Novaclox (Cipla) caps, tabs, injections; Tresmox caps (Sarabhai); Tormoxin plus and Twiciclox (Torrent) and other such.
Comments :
All above arguments for ampicillin and cloxacillin combinations hold in this case also, in addition to the following: dosing pattern of both these antibiotics is different as mentioned in standard medical textbooks: amoxicillin is recommended three times a day whereas cloxacillin is recommended four times a day, thus creating a discrepancy in dosing time schedules.
Recommendations: As above for FDCs of ampicillin and cloxacillin: to be weeded out and can be used concurrently if necessary.
(c)	*FDCs of Metronidazole/Tinidazole plus Diloxanide Furoate/Di-iodohydroxyquinoline (DHQ) combinations*

Brand Name Examples: Dinite (Searle) tabs, suspension; Entamizole (Boots) tabs, syrup; Flagyl-DF (Rhone-Poulenc) tabs; Metrogyl compound (Unique) tabs; Qugyl (Searle) tabs, suspension; Cyloxanid (Biddle-Sawyer) tabs; Wotinex (Wockhardt) tabs; Zoa Forte (Tata- Pharma) tabs and such others.
Comments :
(i) Metronidazole and tinidazole are tissue amoebicides whereas diloxanide furoate and DHQ are luminal amoebicides.
(ii) The standard treatment of invasive amoebiasis is tab. metronidazole (35 to 50 mg/kg/day in the three divided doses) for 7-10 days followed by diloxanide furoate 500 mg three times a day for further 10 days.
(iii) According to Goodman and Gillman (1990) for asymptomatic and non-invasive intestinal amoebiasis, only diloxanide furoate is sufficient. In such patients these combinations will lead to unnecessary intake of metronidazole/tinidazole. In case of invasive intestinal and systemic amoebiasis, including amoebic diseases, metronidazole/tinidazole is given followed by diloxanide furoate (Goodman-Gillman, p.955).
(iv) According to Laurence D.R (Clinical Pharmacology, 1992) treatment with tissue amoebiasis should always be followed by a course of luminal amoebicide to eradicate the source of the infection (p.207).
(v) The combination is recommended nowhere.
Recommendations: Ban all these combinations. Let these drugs be separately available for their appropriate use.
(d) *FDCs of Metronidazole/Tinidazole and Furazolidone*
Brand Name Examples:
Flagyl F (Rhone Poulenc) tabs, suspension; Fumedil-DS (Ethnor) caps; Kaltin-MF(Abbott) suspension; Metrogyl-F (Unique) tabs, suspension; Tini-F syrup (Kopran) and such other products.
Comments :
(i) Metronidazole is primarily an antiamoebic whereas furazolidone is an antibacterial effective against colonic gram negative bacteria. Furazolidone is nowhere mentioned for use in the latest editions of Goodman Gillman (1990) and Clinical Pharmacology by D.R. Laurence (1992). They are perhaps replaced by safer and more effective agents.
(ii) All diarrhoeas/dysenteries are not polymicrobial in origin - not always due to concurrent infection by E.histolytica and colonic pathogenic bacteria. Thus a person suffering from amoebiasis is condemned to take furazolidone and a patient suffering from bacterial dysentery has to take metronidazole/tinidazole unnecessarily. This increases cost of therapy and chances of ADR.
(iii) Most diarrhoeal diseases do not need treatment with antibiotics/antibacterials. Many of them are self-limiting and need only supportive therapy like fluids and electrolytes with ORS.
Recommendations: Ban all formulations containing metronidazole/tinidazole and furazolidone combinations. They may be separately formulated and marketed in appropriate conditions.
2. FDCs of Analgesics with Analgesics/Antiinflammatory drugs
FDCs of Ibuprofen/Ketoprofen/Diclofenac with Paracetamol/Analgin
and such others
Brand Name Examples: Combiflam (Roussel) tabs and suspension; Ibugesic Plus (Cipla) tabs, susp.; Lederflam Plus (Lederle) tabs; Magadol (Alembic) tabs, suspension.; Tribusynth (Astra-IDL) tabs; Zupar (Allenburys) caps, tabs, syrup; Ketonal-D (PCI); Redufin-A (Unique); Cofenac (Protec) tabs; Diclogesic (Torrent) tabs; Diclofam Plus (Max) tabs; Fenaside-P (Nicholas) tabs; and such others.
Comments:
i) i) Ingredients of all these combinations, mainly paracetamol, analgin, ibuprofen, diclofenac, etc., belong to a single category of drugs, i.e., Non-Steroidal Inflammatory Drugs (NSAIDS). Paracetamol and analgin have chiefly analgesic and antipyretic actions. Ibuprofen and diclofenac have mainly anti-inflammatory action in addition to having analgesic and antipyretic effects. All these effects are produced by inhibition of synthesis of prostaglandins. Since the mechanism of action is same, there is no synergism. More over anti-inflammatory action leads to pain relief.
(ii) NSAID combinations are known to cause direct damage to kidney (Clinical Pharmacology, Laurence, 1992, p.469.) Although nephropathy is uncommonly associated with the long-term use of individual aspirin-like drugs, the abuse of analgesic mixtures has been linked to the development of renal injury including papillary necrosis and chronic interstitial nephritis (Goodman-Gillman, 1990, p.643).
Recommendations: All such combinations should be banned. Individual ingredients, except analgin, however may be marketed for use either singly or concurrently in appropriate doses in suitable conditions.
ii) Safer and better alternatives, including injections, for analgin are available. Looking to the dreaded ADR of analgin on bone marrow, its marketing as single agent or combination should be banned.
3) Iron Preparations
a) Haemoglobin containing iron preparations Brand Name Examples: Bio-syn (Gufic) liquid; Dexorange Plus (Franco-Indian) caps and syrup; Globac (Alidac) caps and liquid; Haem Up (Cadila) liquid and gems; Hb-Rich (Merind) liquid; Probofex with Haemoglobin (Wockhardt) syrup; Reditone Plus (Blue Cross) liquid;
Comments :
(i) The source of haemoglobin is blood of animals killed in slaughter houses. This could be dangerous for human use for the fear of causing allergic reactions (foreign proteins), transmission of infections (zoonosis, because blood is a rich medium for bacterial growth), etc.
(ii) Haemoglobin per se is a poor source of elemental iron absorbed by the body. More than half a bottle of any of above preparations will be required for appropriate response in anaemic conditions
(iii) Because of lack of this knowledge on part of patients, and even doctors, it will result into subtherapeutic use and inadequate treatment.
(iv) A six-month course with such preparations will cost approx. Rs.3,650/- as against Rs.55/- (approx.) of treatment with nearly rational preparations of iron-folic acid (Macrofolin-Iron of Glaxo) available in the market.
(v) No standard textbooks of medical sciences or medical journals mention the use of haemoglobin as a drug.
Recommendations:(i) Totally ban the use of iron preparations containing haemoglobin from any source.
(ii) Only preparations containing iron and folic acid (in appropriate amounts) are rational and recommended by WHO. Only such preparations need to be allowed.

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