FIXED DRUG DOSE COMBINATIONS

K.VISHNUVARDHAN BABU

The combination of two different drugs in a single pharmaceutical formulation is known as fixed drug dose combination.

As a rule,

-1.two drugs to be combined should have approximately equal plasma half life and

- 2.the ratio of doses of each component should depend on apparent volume of distribution and plasma concentration.

EXAMPLE

E.g-amoxycillin(t ½-1-2hr,Vd-0.21 L/kg) and clavulanic acid(t ½-1-1.5hr,Vd-0.2 L/kg)hence these can be combined in their standard dose regimen...i.e amoxycillin 500mg+clavulanic acid 125mg can be administered as 1 to 2 tab 8hrly

ADVANTAGES

Convenience in dose schedule and better patient compliance.

Enhanced effect of the combinations

e.g-oestrogen +progesterone.

Minimisation of side effects

E.g-levodopa+carbidopa

CONTD...

Reduction in number of pills improve the patient compliance

FDC can improve compliance in the treatment of chronic infectious diseases.eg-treatment of TB and HIV.

DISADVANTAGES

The dose of any component cannot be adjusted independently.

Pharmacokinetics must not be widely different.

It becomes difficult to identify one particular drug which is causing harmful/beneficial effects.

CONTD...

some fixed dose combinations show more adverse effects

E.g-nimesulide+paracetamol.

One of the drugs in the combination maybe wasteful-E.g-vitamin+iron

There will be increase in price if unnecessary drugs are included.

-e.g-ibuprofen+paracetamol+caffeine

CONTD...

In FDC there is always a chance that individual medicines may not be present in adequate amounts e.g-multivitamins

Incompatible pharmacodynamics e.g-combination of antihistaminic and antidiarrhoeal is dangerous as antihistaminic action may mask other symptoms.

RATIONAL FIXED DOSE COMBINATIONS

Improved patient compliance-simplified disease management for chronic diseases like HIV,diabetes,hypertension,asthma etc

Better efficacy-synergistic mechanism,improved ADME and drug resistance.

Simplified/cost effective handling and distribution-mainly for HIV drugs.

EXAMPLES OFRATIONAL COMBINATIONS

Amoxycillin+clavulanic acid

Ampicillin+sulbactam

Ferrous salt+folic acid

Rifampicin+isoniazid+pyrazinamide-150mg+75mg+400mg

Levodopa+carbidopa-100mg+10mg or 250mg+25mg

CONTD...

Levodopa+carbidopa-100mg+10mg or 250mg+25mg

Lamivudine+zidovudine

Abacavir+lamivudine+zidovudine

IRRATIONAL THERAPY

- Results in

Adverse drug reactions

Emergence of resistant microorganisms

Financial complications-more costly

Masking/confusing/delaying the correct diagnosis

REASONS FOR IRRATIONALUSE OF DRUGS

1. Lack of information related to indications & safety of drugs.

2. Faulty & inadequate training & education of medical graduates

3. Poor communication between health professional & patient

CONTD...

4. Lack of diagnostic facilities/Uncertainty of diagnosis:

5. Demand from the patient

6. Defective drug supply system & ineffective drug regulation

7. Promotional activities of pharmaceutical industries

HAZARDS OF IRRATIONAL USE OF DRUGS

Irrational use of drugs may lead to:-

1. Ineffective & unsafe treatment

2. Exacerbation or prolongation of illness.

3. Distress & harm to patient

4. Increase the cost of treatment

EXAMPLES OF IRRATIONAL DRUG THERAPY

1.Nimesulide+paracetamol-FDC of analgesic,anti inflammatory and antipyretic results in increased hepatotoxicity

Moreover,there is no synergism when two drugs acting on the same enzyme are combined.Thus combining two NSAIDS or NSAID with analgesic like paracetamoldoesnot improve the efficacy or potency of treatment.

CONTD...

2. Ampicillin + Cloxacillin

Ampicillin is effective against Gram negative bacilli but Cloxacillin is an Anti-staphylococcal penicillin and not effective against Gram negative bacilli. Mixed Gram negative and Staphylococcal (Gram positive) infection rarely coexists

CONTD...

3.Gastrointestinal drugs-such as domperidone+rabeprazole-increased incidence of rhabdomyolysis.

4.Antacid +antianxiety drug

the acid peptic disease is rarely associated with psychosomatic basis.so,there is no justification of combining antianxiety drug with antacid

CONTD...

5. H2 Blocker (Ranitidine) + Antispasmodic Drug (Dicyclomine)

-The pain of peptic ulcer will subside only with reduction in gastric acid in stomach by use of H2 blocker (Ranitidine) or proton pump inhibitor drugs (Omeprazole, Pantoprazole or Lansoprazole). So there is no justification in combining H2 blocker (Ranitidine)

CONTD...

6.Antacids with antianxiety drugs-The simultaneous use should always be avoided as antacids reduce the absorption of antianxiety drugs.

CONTD...

7.Mucolytic Agent + Antibacterial

There is no justification in combining mucolytic agent with antibacterial, as thick secretions in respiratory tract are always not due to respiratory infections. Also the antibacterial therapy always does not require an associated dose of mucolytic agent.

CONTD...

8. Metformin + Glimepiride + Pioglitazone

Metformin is indicated drug in obese type -2 diabetes mellitus whereas Sulfonylurea (Glimepiride) is indicated drug in non-obese type-2 diabetes mellitus. As per pharmacological principle, other drug should be added only when monotherapy fails.

CONTD...

Metformin (biguanide) is to be administered after meal whereas Glimepiride (sulfonylurea) drug is to be administered before meal, therefore even when both the drugs are required, it would be better to administer them separately. Pioglitazone is indicated in suspected cases of insulin resistance. So, the combination of all these drugs in one formulation is irrational.

CONTD...

9. Antibacterial + Antiamoebic Combinations:

-In bacterial diarrhoea only anti-bacterial drug is effective and antiamoebic drug is useless and viceversa. Amoebiasis and bacterial diarrhoea rarely coexist. The therapy should be based on the diagnosis to reduce the cost of treatment.Only one drug of the combination would be effective and the other one would be useless.

CONCLUSION

Rational combinations- can be of immense help to the health care system and they improve the quality of life . Such combinations (for example, antitubercularand antiretroviral combinations) are used frequently. However the irrational fixed dose combination products are considered to be equally harmful

CONTD....

According to the WHO Expert Committee, combination drugs should be only used when there are no alternative of single drugs available or cost effective for the purpose. Combination drugs increase the risk of side effects and may also needlessly increase the cost. Combination drugs are irrational also because their stability is doubtful, reducing the efficacy of many preparations.

EXERCISE

A doctor has diagnosed acute amoebic dysentery in an adult patient and prescribed a combination of norfloxacin 400 mg + metronidazole 500 mg to be taken orally twice daily for 5 days. Analyze the given combination using rationality criteria.

Justification A number of combinations available for given

problem are irrational because patient suffers only from one type of diarrhea and therefore use of such a combination adds to the cost, adverse effects, and may encourage resistance.

CONTD...

EFFICACY

-FDCs should be avoided when one drug is adequate for the said condition. Metronidazole is effective in acute amoebic dysentery and no need to give norfloxacin. Therefore, metronidazole followed by diloxanidefuroate to get rid of the cysts that may remain after the metronidazole therapy is the treatment part of this case.

CONTD...

Cost effectiveness Rational therapy calls for the prescription of less-

costly single ingredient drugs more often. Metronidazole is to be administered as 750 mg three times a day for 5 days while the combination of norfloxacin 400 mg + metronidazole 500 mg is given twice daily for 5 days in acute amoebic dysentery. The average minimal cost of therapy of acute amoebic dysentery with metronidazole and with combination of norfloxacin + metronidazolewould be Rs. 10.00 and Rs. 45.00, respectively.