Introduction

Fixed Drug Combination products have been increasingly used either to improve compliance or to benefit from the added effects of the two medicinal products given together. The proposed combination should always be based on valid therapeutic principles. In addition, it is necessary to assess the potential advantages (e.g. product rapidly effective, higher efficacy or equal efficacy and better safety) in the clinical situation against possible disadvantages (e.g. cumulative toxicity), for each fixed combination product and for each dose of the fixed combination product. Potential advantages may also include the counteracting by one substance of an adverse reaction produced by another one and the simplification of therapy. Clinical developments should correspond to each situation/intended claim. In addition, particular attention should be drawn to the doses of each active substance in the fixed combination product. Each dose combination should be carefully justified and clinically relevant (e.g. in cases when each component of the fixed combination has several possible dosages, dosages that have shown benefit on hard clinical outcomes may be preferable for the fixed combination than the dosages effective on surrogate endpoints only). Potential advantages of fixed combinations include one of the following: a) an improvement of the benefit/risk assessment due to : i. addition or potentiation of therapeutic activities of their substances, which results in: a level of efficacy similar to the one achievable by each active substance used alone at higher doses than in combination, but associated with a better safety profile or a level of efficacy above the one achievable by a single substance with an acceptable safety profile. ii. the counteracting by one substance of an adverse reaction produced by another one. b) a simplification of therapy which improves patient compliance. Disadvantages of fixed combinations include : i. the fact that even a combination which meets the needs of the average patient is unlikely to be ideally adjusted for the needs of each individual patient; ii. the addition of the different adverse reactions specific to each substance. General rules Combinations, in principle, may not be considered rational if the duration of action of the substances differ significantly. This may not necessarily apply where it can be shown that the combination is clinically valid despite differences in this respect, e.g. if one substance is intended to enhance absorption of the other or where the substances are intended to exert their effects successively. Each substance of the fixed combination must have documented contribution within the combination. The inclusion of a substance to counteract an adverse reaction of another substance may be considered justified, but only if the adverse reaction is a serious or a commonly occurring one. The inclusion of a substance intended to produce unpleasant adverse effects as a means of preventing abuse in undesirable. Substances having a critical dosage range or a narrow therapeutic index are unlikely to be suitable for inclusion in fixed combinations. Indications The indications claimed for a fixed-combination medicinal product should be such that the presence of each active substance makes a contribution to the claimed effect. The product should be formulated so that the dose and proportion of each substance present is appropriate for the intended use. An indication must be a well-recognised disease state, modification of a physiological state, dysfunctional state, syndrome or pathological entity. The individual substances of a fixed combination may be intended to relieve simultaneously different symptoms of such a disease state. In this case, it should be a prerequisite that these symptoms regularly occur simultaneously in a clinically relevant

intensity and for a relevant period of time. It will not be proper to regard each individual symptom as an indication for the fixed combination, since it may also occur in other diseases and for treating this symptom alone the other substances may be irrelevant. Fixed combination medicinal products may be indicated in different situations: i. in first line therapy, for patients receiving previously neither of the substances 2. in second line therapy, when monotherapy has not demonstrated a satisfactory benefit/risk ratio. The applicant should clearly state if the claimed indication is first line, second line therapy or other uses and the clinical development should be performed accordingly. Pharmacodynamic : Frequently, the addition or the potentiation of the pharmacodynamic effects of the various substances may constitute the rationale of the fixed combination. Pharmacokinetic : must demonstrate that the various substances do not affect each others respective pharmacokinetic patterns. In some cases, however, a pharmacokinetic interaction (i.e. combination with a metabolism inhibitor) constitutes the rationale of the fixed combination.

Rationale for Combination Therapy All drugs have unwanted side effects in addition to the desired therapeutic effect. The idea of combining two or more drugs with complimentary modes of action is to produce additivity of the desired therapeutic effect but not of the side effects. For example, Consider the combination co-trimoxazole (trimethoprim + sulfamethoxazole). The 2 FDC drugs in this, block 2 consecutive steps in biosynthesis of essential nucleic acids and proteins in bacteria, thus killing bacteria more effectively than each drug could have done independently. Advantages of Fixed Dose Combinations Combination medicines have the advantages of combination therapy as well as advantages related to 1. reducing the number of pills to be taken. 2. Reduced administration costs stem from simplified packaging, fewer prescriptions, and lesser dispensing time and cost. 3. Reducing the number of pills diminishes the complexity of the regimen, so that improved patient adherence is expected with FDCs. 4. FDCs can improve compliance in the treatment of chronic infectious disease, where partial adherence can lead to the development of drug-resistant strains, treatment failure and a threat to public health. i.e., An example of this is the treatment of TB and HIV. 5. The side effects of one medicine can be reduced by combining it with another medicine in a FDC. (e.g.carbidopa reduces the side effects of levodopa) 6. The efficacy of one medicine can be synergistically increased, by combining it with another. (Some examples of this are the combination of estrogen and progesterone in oral contraceptives; the combination of sulfamethoxazole and trimethoprim; pyrimethamine and sulfadoxine for the treatment and prophylaxis of falciparum malaria). Disadvantages of Fixed Dose Combinations: 1. Flexibility of dosage (titration of dose of medicine/s to suit individual patients) is not possible with fixed combinations (e.g. FDC of 10mg Atorvastatin + 5mg Amlodipine).

2. Fixed drug combinations increase the price of the medication if unnecessary drugs are included. (for example, FDC of Ibuprofen + Paracetamol + Caffeine) 3. One of the drugs in the combination may be superfluous or wasteful. (for example, the Combination of vitamins with iron.) 4. Most combinations do not have a sound rationale, (for example, the FDC of more than one analgesic). 5. With combination medicines, the incidence of adverse effects increases, (for example, the FDC of more than one NSAID). 6. In FDCs, there is always a chance that individual medicines may not be present in adequate amounts, (for example, multivitamins). 7. Incompatible pharmacodynamics (FDC of antihistaminic with an antidiarrheal is dangerous. The antihistaminic action may mask other symptoms and make accurate diagnosis and treatment difficult). 8. The physician's and the pharmacist's ignorance of contents and composition of formulation can cause serious problems. 9. It is difficult to identify/pinpoint which medicine in the FDC has caused an adverse effect. 10. These fixed dose combinations can lead to polypharmacy. 11. Dose of one ingredient cannot been altered. 12. Different pharmacokinetic properties can pose difficulty in frequency of administration and in case of development of an ADR. 13. It is difficult to withdraw the suspected drug alone. 14. 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. 15. 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 16. 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) 17. 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). Irrational drug combinations:
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. 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.

Rational combinations recommended by WHO The W.H.O. through its Essential List recommends only the following FDCs: Amoxicillin + Clavulanic acid Artemether + Lumefantrine Benzoic acid + Salicylic acid (external use) Carbidopa + Levodopa Ethinylestradiol + Levonorgestrel Ethinylestradiol + Norethisterone Ferrous salt + Folic acid Imipenem + cilastatin Iopinavir + Ritonavir Isoniazid + Rifampicin Isoniazid + Ethambutol Isoniazid + Thioacetazone Lidocaine + Epinephrine Neomycin+ Bacitracin (external use) Rifampicin + Isoniazid + Pyrazinamide Rifampicin + Isoniazid + Pyrazinamide +Ethambutol Sulfadoxine + Pyrimethamine Sulfamethoxazole + Trimethoprim