In active substance, dose and behaviour in the body, yes: an authorised generic is equivalent to the reference medicine. In excipients, name, colour, tablet shape and packaging, it does not have to be. That is the whole difference, and understanding exactly where the boundary sits resolves almost every doubt raised by a change of box at the pharmacy.
The confusion comes from “the same” being used with two different meanings. A generic is not a physical copy of the original: it is a different medicine that has had to prove it behaves the same inside you. European regulation does not require cloning the tablet, it requires proving that the amount of drug reaching your blood, and the speed at which it arrives, are the same.
What the law requires
The legal definition is in Spain’s Royal Decree 1345/2007, which transposes the European directive. A generic medicine must meet three conditions:
| Requirement | What it means in practice |
|---|---|
| Same qualitative and quantitative composition in active substances | The same molecule and the same amount. Different salts, esters, isomers or derivatives of an active substance are considered the same active substance |
| Same pharmaceutical form | With one exception: among immediate-release solid oral forms, capsules and tablets are considered interchangeable |
| Demonstrated bioequivalence | Through pharmacokinetic bioavailability studies against the reference medicine |
The letters EFG you see after the name stand for “Equivalente Farmacéutico Genérico” and are assigned by the Spanish Agency of Medicines and Medical Devices (AEMPS) only to medicines meeting that legal definition. It is not marketing decoration: it is a regulatory classification.
What a bioequivalence study is
Here is the heart of the matter. The study is normally done in healthy volunteers, at a single dose, with a crossover design: each person takes one formulation first, a washout period is allowed so the drug clears the body, and then they take the other. That way each volunteer is their own control.
Three parameters are measured from the blood concentrations:
- AUC (area under the curve): how much drug arrives in total. This is the measure of the amount absorbed.
- Cmax: the maximum concentration reached.
- tmax: how long it takes to reach that peak.
The generic/reference ratio is then calculated for AUC and Cmax. For the agency to accept it, the 90% confidence interval of that ratio must fall entirely within the 80.00-125.00% range. The European guideline additionally requires a minimum of 12 evaluable subjects.
That the criterion is the confidence interval and not the mean is the part lost in almost every argument about this. It is not enough for the average result to be close to 100%: the entire statistical uncertainty has to fit inside the range. A study with few volunteers or high variability produces a wide interval that falls outside the margin, and the generic is not authorised. In practice this pushes laboratories to keep the mean very close to 100%, not at the edges.
The 80% versus 125% myth
The most circulated argument is this: if one generic can be at 80% and another at 125%, then two generics could differ by 45%. The AEMPS itself has dismantled this in writing, and the reason is geometric.
If the reference product is 100% and the confidence interval of the ratio has to fit within a ±20% margin, the reference product is never at one extreme: it sits in the middle. Each generic is compared against the same central standard, not against the other generic. Adding the two theoretical extremes describes a situation the statistical design itself prevents.
There is a second fact almost nobody takes into account: the innovator laboratory also modifies its formulations and manufacturing processes over the years, and to justify those changes it uses exactly the same bioequivalence studies and the same range. The difference is that those changes are not announced and the packaging does not change, so nobody perceives them.
When the margin narrows
The 80-125% does not apply to everything. For active substances with a narrow therapeutic index — those where a small difference in concentration does have clinical consequences — the European guideline tightens the AUC acceptance criterion to 90.00-111.11%, and also that of Cmax when the peak matters for safety or for monitoring levels.
In Spain the precaution goes further and reaches the counter directly. Order SCO/2874/2007 establishes which medicines cannot be substituted at the moment of dispensing without the express authorisation of the prescriber:
- Biological medicines: insulins, blood products, vaccines and biotechnological medicines
- Narrow therapeutic index active substances, except by the intravenous route: acenocoumarol, carbamazepine, ciclosporin, digoxin, metildigoxin, phenytoin, flecainide, lithium, tacrolimus, theophylline, warfarin, levothyroxine, sirolimus and everolimus in the transplant indication
- Active substances under special medical control: systemic isotretinoin and acitretin, acetohydroxamic acid, thalidomide, clozapine, pergolide, cabergoline, vigabatrin and sertindole
- Respiratory medicines given by inhalation
If you take any of these, the pharmacist cannot change the brand on their own initiative even if a cheaper generic exists. That is not a professional preference: it is a legal restriction.
Where they genuinely do differ
This is also worth being clear about, because real differences exist and are legitimate:
- Excipients. They can be different. Sometimes because the original’s excipient is patented. They are always of pharmaceutical grade and evaluated, but if any of them requires precautions (for intolerances or allergies), that warning must appear on the labelling and in the leaflet. If you have reacted to a specific excipient, that is the point to check when the laboratory changes.
- Appearance and name. Colour, shape, tablet size, score line, packaging and brand name can all vary. None of that affects the drug’s activity, but it can disorient someone who has spent years identifying their tablet by its shape.
- Indications. If the original retains a use patent on some indication, that indication cannot appear in the generic’s leaflet even though the active substance is the same.
What does not change are the quality guarantees: the same Good Manufacturing Practice, the same complete chemical and pharmaceutical documentation, the same plant inspections and the same pharmacovigilance system after marketing.
A generic is not the same as a biosimilar
Two categories that often get mixed up. A biosimilar is the non-original version of a biological medicine — proteins produced by living organisms — and it does not meet the definition of a generic precisely because the production process makes it impossible to reproduce the molecule identically. It follows a different and more demanding authorisation route. A hybrid medicine is another category again: it relies partly on the original’s data and partly on new data, for example when the dose or route of administration changes.
When to ask
Talk to your doctor or pharmacist if:
- You have had an allergic reaction or digestive intolerance that appeared just as the laboratory changed, even though the active substance is the same
- You take acenocoumarol, levothyroxine, lithium, digoxin, an antiepileptic or an immunosuppressant and you have been handed a different box from the usual one
- You use an inhaler and are offered a different device: the inhalation technique changes between devices and that does alter the dose reaching the lung
- You notice a loss of control of your condition (blood pressure, blood sugar, INR, seizures) coinciding with a change of medicine
- You are left unsure whether two different boxes contain the same thing: taking them to the pharmacy and asking avoids doubling a dose by mistake
This information is for general education and does not replace assessment by a healthcare professional. Sources: AEMPS — Regulation of generic medicines: evidence and myths (Inf Ter Sist Nac Salud 2010;34:71-82), AEMPS — Questions and answers on Royal Decree 1345/2007, EMA — Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1), EMA — Questions and answers on generic medicines and BOE — Order SCO/2874/2007, consolidated text.