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Medical Science Monitor Basic Research


eISSN: 2329-0358

Generic substitution of immunosuppressive drugs – requirements for an equivalent product

A. Johnston, D. W. Holt

Ann Transplant 2008; 13(1): 31-31

ID: 880185

Available online:


The impact of small changes in formulation were not considered important until the late nineteen sixties when, due to frank over dosing of large numbers of cardiac and epileptic patients, it became apparent that changes in excipients and even particle size could affect the bioavailability dramatically. These occurrences led to the introduction of bioequivalence guidelines and the need for manufacturers to demonstrate that their products were bioequivalent to existing products. A drug is considered to be bioequivalent to a listed drug if the rate and extent of absorption of the new drug formulation does not show a clinically significant difference from the rate and extent of the listed drug formulation. Regulatory approval requires that the confidence interval for average bioequivalence should lie within the range of 80-125% of the reference drug. It is recognised that the CPMP and FDA bioequivalence criteria may not be suffi cient for critical dose drugs and some regulatory authorities, for example Health Canada, have strengthened their criteria by narrowing their confidence intervals to 90 to 112%. However, to conform to the current bioequivalence guidelines pharmacokinetic studies need only be carried out in healthy people. But, ideally, alternative formulations of critical dose drugs should not only establish simple bioequivalence to an original formulation, but also show similar effects in terms of absorption and clinical response in actual patients. Parameters such as dose, metabolism, age, transplant type, disease, time-dependent kinetics, and time since transplant, should all be considered. Such studies would have to be carried out initially in healthy volunteers and then in transplant patients - looking at different patient groups, de novo and stable patients, and a wide age span. Only then would it be possible to gauge if the formulations were indeed interchangeable and not merely "bioequivalent''. When discussing the interchange of one manufacturer's drug product for another's containing the same active ingredient a distinction should be made between "generic substitution" and "generic prescribing". The former is an automatic substitution of one make of drug for another whereas the later is about making a choice to substitute one brand for another. For many drug classes this may seem an unnecessary distinction but for critical dose drugs it is an important one since a small change in medication may result in a change in the concentration of the drug in a patient's blood and this could result in increased toxicity or decreased efficacy. Either way, if unmonitored, and therefore unchecked, the patient's health is compromised and they may suffer adversely. In conclusion, multiple formulations of critical dose immunosuppressive drugs are now available. How these products compare to existing formulations, particularly in terms of the risk of acute rejection and side effects, is not clear. Therefore it is not advisable to change formulations unless under close supervision and monitoring by a specialist. These costs must be borne in mind when evaluating potential cost savings made by generic prescribing (substitution).

Keywords: bioequivalent, Metabolism, immunosuppressive drugs