A generic medicine is defined as a product having the same qualitative and quantitative composition in active ingredients, as well as the same pharmaceutical form, as the reference medicine and whose bioequivalence has been shown by adequate bioavailability studies. Bioavailability is defined as the amount and speed at which the active ingredient is absorbed from a pharmaceutical form and reaches the site of action biophase. Bearing in mind that an active ingredient is in balance between systemic circulation and the site of action, it is assumed that drug values in blood represent drug bioavailability. Bioavailability is assessed using pharmacokinetic parameters, including: the area under the curve AUC , maximum concentration Cmax and time to maximum concentration Tmax. Bioequivalence is the comparison between the bioavailability of a medicine under study and the bioavailability of a reference drug.
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A generic medicine is defined as a product having the same qualitative and quantitative composition in active ingredients, as well as the same pharmaceutical form, as the reference medicine and whose bioequivalence has been shown by adequate bioavailability studies.
Bioavailability is defined as the amount and speed at which the active ingredient is absorbed from a pharmaceutical form and reaches the site of action biophase. Bearing in mind that an active ingredient is in balance between systemic circulation and the site of action, it is assumed that drug values in blood represent drug bioavailability.
Bioavailability is assessed using pharmacokinetic parameters, including: the area under the curve AUC , maximum concentration Cmax and time to maximum concentration Tmax.
Bioequivalence is the comparison between the bioavailability of a medicine under study and the bioavailability of a reference drug. To conduct bioequivalence studies, blood is collected at several time points after administering the product, according to the drug's half-life.
The concentration of the active ingredient in blood is then measured to estimate bioavailability kinetic values. A local or topical action medicine is a product which is applied locally and assumed to act on the site where it is administered. Systemic effects, if any, should be considered as side effects.
Local action medicines include dermatological products such as creams and ointments , inhaled products, eye and ear drops, nasal products and products administered to the oral, vaginal or rectal cavities with a local effect.
The main challenge in the development of generics of local or topical action medicines is that no bioavailability studies can be performed to compare plasma concentration profiles between reference and generic formulation drugs. Since the effect is produced in mucous membranes or the skin, plasma concentrations are either not high enough to allow drug levels to be determined or, if high enough, they are too small and irregular.
For eye drops, nasal sprays and cutaneous solutions, bioequivalence is accepted if the drug is in the same solution aqueous or oily and contains the same active ingredient concentration as the reference product. Minor differences in excipient composition are accepted whenever pharmaceutical properties of the study medicine and the reference medicine are identical or essentially similar.
Any qualitative or quantitative difference in excipients must be satisfactorily explained in terms of its influence in therapeutic equivalence. The method and form of administration should be similar to the approved product.
The US Food and Drugs Administration FDA 1 requires that study medicines contain the same active and inactive ingredients at the same concentration as the reference product. No differences in excipient composition are accepted.
However, a laboratory may apply for approval of a medicine that differs from the original, identifying and characterizing the differences and providing information to show that differences do not affect drug safety 2.
Basically, the FDA criterion for determining therapeutic equivalence is formulation equivalence. Why do generics manufacturers not copy the original medicine exactly? In one word: patents. On average, each medicine comprises five or six patents. To avoid violating patents, generics manufacturers intentionally change preservatives or the pH, although they never really know for sure how the original product is manufactured.
Some laboratories manufacture both the original medicine and the generic. Bearing all the above in mind, a key question arises: In face of the European Medicines Agency, why does the FDA require all active and inactive components of a generic ophthalmic medicine to be exactly the same as in the reference product? The FDA 1 considers that: 1 Changing the excipients or inactive components of a medicine can have a significant effect both on drug efficacy and safety.
Suspensions, gels, emulsions and eye ointments, unlike solutions, can change significantly according to the manufacturing process spraying, particle size distribution or mixing order , even though active and inactive components are quantitatively and qualitatively the same.
FDA criteria for determining clinical efficacy in these medicines vary according to the pharmacological group and are based on parameters or measures used to establish the efficacy of the innovator drug. For instance, in ocular hypotensive medicines, equivalence is determined if the difference measured between both products is lower than 1. In this case, the clinical trial must include basal intraocular pressure measurements as well as at week 1, 6 and 12, at least at peak and trough times for the active ingredient.
Therefore, there are: anti-infectives, corticosteroids, non-steroidal anti-inflammatory agents NSAIDs , antiglaucoma drugs, fixed combinations, antiallergic agents, mydriatics and cycloplegics and anaesthetics. Tabla 1. Porcentaje de principio activo y excipientes en diferentes colirios antiglaucomatosos. Eye drops contain multiple excipients: 1 a liquid, aqueous more rarely, oily vehicle; 2 preservatives; 3 pH-adjusting agents; 4 antioxidants; 5 viscosity agents; 6 buffers.
The main purpose of preservatives is to inhibit bacterial contamination. Some surfactant preservatives also contribute to keeping lipophilic drugs in solution, such as prostaglandin analogues. This causes the drug to achieve higher levels in the aqueous humour with the same concentration brimonidine 0.
The reason is that preservatives such as BAK prevent the pH from increasing beyond 6. Thus, changing the preservative and increasing the pH improved the corneal penetration of brimonidine and increased the drug's concentration in the aqueous humour. Figura 2. Concentraciones de brimonidina en humor acuoso en el tiempo. J Ocul Pharmacol Ther. Viscosity-modifying agents increase drug contact time with the ocular surface, thus improving absorption. By raising the contact time, these agents reduce nasolacrimal absorption and improve systemic safety.
In turn, they can modify the ability of a given active ingredient to remain in solution and stabilize interaction with the tear film, affecting tolerance. Therefore, Meseguer et al. Tabla 2. Dickstein et al. Subjects exercised maximally on a cycle ergometer four times with ten-day intervals. The serum timolol concentrations were 0.
The change from baseline in resting heart rate was The change from baseline in peak heart rate was These differences are statistically significant. Figura 3. Comparison of aqueous and gellan ophthalmic timolol with placebo on the hour heart rate response in patients on treatment for glaucoma. Am J Ophthalmol. Although both treatments caused reductions in resting and exercise heart rate, timolol gellan was associated with significantly lower reductions.
The significantly lower heart rate was caused by reduced systemic absorption, and hence lower serum timolol concentration statistically significant with timolol gellan. Temperature affects active ingredient concentration in eye drops. Kahook et al.
All medications, both brand-name and generic, showed a reduction in active ingredient concentration and BAK when exposed to temperatures above those in the information leaflet. The increased basal active ingredient concentration could be a strategy to compensate the known degradation of drugs over time to levels below their optimal dose, including at room temperature. The timolol-dorzolamide combination in both brand-name and generic medications is relatively resistant to degradation.
Bottles of both generic medications had higher levels of particulate matter compared to brand-name versions. The exact nature of the particulate matter is unknown.
Whereas some look solid, others seem to be fibrillary in nature. The origin of particulate matter is unknown and could result from contaminants, active ingredient precipitates or container material.
It is not known whether particulate matter can have clinical repercussions on the ocular surface with normal use. Tabla 3. A comparison of active ingredients and preservatives between brand name and generic topical glaucoma medications using liquid chromatography-tandem mass spectrometry. Curr Eye Res. Generic and innovator medications can also differ in bottle design, viscosity, surface tension and drop volume. Mammo ZN et al. Tabla 4. Generic versus brand-name North American topical glaucoma drops.
Can J Ophthalmol. Clinical differences between generic and brand-name anti-inflammatory ophthalmic medications. Corneal complications were seen after instillation of diclofenac post-operatively after routine ophthalmic procedures. A class effect was considered The complications were eventually associated with a generic of a certain brand, which was rapidly withdrawn from market Which medication component was responsible for corneal complications was not reported.
Figura 4. Corneal complications associated with tropical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. One problem with the generic drug suspension manufactured by Sabex Pharmaceutical Quebec is that it would require at least 70 shakes to obtain an homogenous suspension Another generic from Falcon Laboratories Forth Worth caused occlusion of the eye drop bottle tip potentially due to a prednisolone acetate precipitate In sum, several researchers 12,14 have noted different problems in generic prednisolone acetate formulations, which were associated with suspension characteristics and forming of precipitates.
Among these, are changes in suspension homogeneity, occlusion of the eye drop bottle tip and significantly lower concentration of the active ingredient in each drop. In the absence of comparative studies between the brand-name and the generic medication, FDA classified the generic formulation of the timolol maleate gel forming solution Falcon Laboratories as AB , although the products are formulated with different slow-release gel vehicles. Corneal contact time is different for both medications, as well as inactive excipients and preservative concentrations.
Stewart et al. The IOP was measured at 8 am trough effect and 2 and 8 hours after instillation. No statistically significant differences were observed between both medications at 8 am, nor 2 hours after administration. However, 8 hours after instillation the IOP was Both safety and vision recovery time were similar in both groups. Narayanaswamy et al. A total of 30 patients were included. In both groups, all patients showed week IOP values lower than 21 mmHg, i.
ANTIGLAUCOMATOSOS OFTALMICOS PDF
Objective: To determine the mean drop volume produced by artificial tear solutions in different inclination angles and to determine the mean cost of the treatment. The mean number of drops in each bottle was determined and a pharmacoeconomic evaluation of the drops was made. Results: The drop volume ranged from Conclusion: None of the collyria studied presented ideal drops for human eyes, leading to a waste of the product and higher cost for the manufacturer and the consumer. In the ophthalmic practice, the main route of drug administration is made by eyedrops. The official medical eyedropper, according to the American Pharmacopoeia, presents an outter diameter of 3 mm and dispenses 20 drops of distilled water per mL at a temperature of 25oC by positioning the eyedropper perpendicular to the person that will receive the drop 1.
Are generics and brand-name medicines the same?*
Ribeiro Franca. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost Latoprost in subjects with primary open angle glaucoma or ocular hypertension. When patients ask about replacing a branded product with its generic counterpart, all we can honestly say as doctors is that the new generic medicine has not been studied, analysed or compared to the original medicine, and so we cannot know whether it will act in a similar way — in other words, whether both medicines are equally effective. Whereas some look solid, others seem to be fibrillary in nature. Te average number of droplets contained in each vial was also determined, taking into account the antiglaucomattosos volume of each drop and the total volume of the vial as advertised by the manufacturer on the product label The change from baseline in resting heart rate was Considering the therapeutic equivalence of tear solutions, the cost minimization analysis is a simple way of economic evaluation in which only the costs are subjected to comparisons because the efficacy or the effectiveness of the comparable alternatives are equal 11, The change from baseline in peak heart rate was Some surfactant preservatives also contribute to keeping lipophilic drugs in solution, such as prostaglandin oftslmicos.
To evaluate the intra and inter variations of eye drops volume dispensed from bottles available on the market. Five bottles of lubricant eye drops were studied and nineteen volunteers participated in this study. Five drops of each vial were individually weighed with the tube perpendicular to the balance, using the first and second fingers of the right hand, so that the pressure was applied only in the middle of the flask. All eye drops bottles showed a statistically significant variation on masses of the drops obtained by examiners when compared with the standard average weight of 0.