A quick excursus from diagnosis to therapy: let's take a brief look at the pathology taking advantage of the clinical and surgical expertise of Dr Antonello Rapisarda, Director of the Complex Operative Unit of Ophthalmology at the Garibaldi Hospital in Catania.
Glaucoma is usually asymptomatic in its early stages, what are the most advanced diagnostic tests for a correct diagnosis and how important is it to detect the disease at an early stage?
Glaucoma (GL) represents a broad spectrum of ocular diseases, characterised by progressive damage to the optic nerve and retinal nerve fibre layer with associated visual field deficit. This disease is multifactorial and the main risk factor is elevated intraocular pressure; associated with this are other factors such as family history, age, race, myopia and systemic vascular abnormalities.
The morphological and functional damage produced by glaucoma is irreversible, so early diagnosis is essential in order to initiate appropriate therapy before permanent visual deficits set in. The basic diagnosis of GL is based on a complete ophthalmic examination (anamnesis, visus, anterior segment examination, gonioscopy, tonometry and fundus with a focus on optic nerve papilla analysis), visual field examination and corneal thickness assessment (pachymetry). This diagnostic process, which still today represents the "gold standard" in the diagnosis and evaluation of the progression of glaucomatous damage, has the limitation of not allowing the detection of the pathology in its early stages: the functional damage highlighted in the visual field in fact follows the morphological lesions of the optic nerve by a long way.
In the last decade, high-tech ('hi-tech') instrumental methods, such as OCT, HRT and GDX, have been developed that allow the detection of changes in the optic nerve papilla and the retinal nerve fibre layer. Such 'hi-tech' examinations are a valuable aid for the early diagnosis of glaucoma and a more accurate assessment of the progression of the disease.
What is the first therapeutic approach in cases of glaucoma?
Even today, the fundamental therapy of glaucoma is based on reducing eye pressure with pharmacological, laser or surgical methods. However, it must be borne in mind that the purpose of glaucoma therapy should not be limited to the control of endocular tension alone, but must take into consideration the whole individual. In fact, as highlighted by the European guidelines, the purpose of glaucoma treatment is to maintain the patient's quality of life at an acceptable economic cost.
Maintaining quality of life involves the preservation of visual function, low local and systemic side effects and a treatment regimen that is as simple as possible. The concept of sustainable cost is equally important and pertinent in the light of the limited economic resources of the national health service: this does not imply that the therapeutic choices should consequently be oriented towards cheap drugs or treatments, but rather indicates that the general management of the disease should be optimised in accordance with costs (employing monotherapies, using effective treatments that reduce the need for excessive specialist controls, avoiding functional deficits, etc.).
The first therapeutic approach to glaucoma, as is well known, involves the administration of topical hypotonic drugs. Recalling the general principles outlined above, an anti-glaucomatous drug must have the following characteristics:
- a high hypotonic action in order to reach the 'target' pressure value;
- constant effectiveness over time, both over 24 hours and in the long term;
- high local and systemic tolerability;
- effectiveness with the minimum of administrations (dosage) to ensure good 'compliance'.
Accordingly, drug therapy should be started as monotherapy, thus allowing its effectiveness to be verified, reducing costs and complications and improving 'compliance'. If the drug is effective in achieving the 'target' pressure and well tolerated, the same therapy should be continued; conversely, if the drug is ineffective and/or not tolerated, it should be replaced with another one. Only in the case of a molecule that is tolerated and effective, but not able to reach the target pressure, should a therapeutic combination with another drug be used.
The European Guidelines suggest all hypotensive drugs in the first instance, and studies identify prostaglandins as the most effective topical drugs for reducing intraocular pressure. What is your clinical experience in this regard?
Prostaglandin analogues (PGs), as is well known, constitute a category of molecules with a particular and unique mechanism of action among ocular hypotensive drugs, increasing uveoscleral outflow. These drugs, of which latanoprost is the progenitor, have revolutionised the management of glaucoma by shifting it increasingly towards pharmacological rather than surgical treatment. Numerous clinical studies have highlighted the advantages in terms of clinical efficacy of PG over other categories of hyponatal drugs. In fact, prostaglandin analogues express all those characteristics (outlined above) of efficacy, tolerability and 'compliance' that are sought in an antiglaucomatous molecule. Moreover, PGs, thanks to their particular mechanism of action, are extremely suitable for combination with all other hyponotising drugs.
Accordingly, prostaglandin analogues are now irreplaceable molecules in our clinical practice for the pharmacological management of glaucoma.
There are more than 10 latanoprost equivalents on the market, marketed by different pharmaceutical companies. What is your approach towards equivalent drugs?
First of all, it is very important to clarify the terminology, definition, efficacy and cost characteristics of a generic or equivalent drug according to the National Health Service (NHS).
A generic drug is defined as a drug that contains the same amount of active ingredient and has the same bioavailability as another branded drug with an expired patent.
The definition of equivalent medicine was introduced in Italy by Law 149 of 2005. The change of name to "equivalent'. was ordered by the Ministry of Health, in order to avoid the deadline 'generic' could be considered somewhat reductive for this type of drug.
However, both terms are correct and identify a medicine that contains the same amount of active ingredient and has the same bioavailability as another branded medicine with an expired patent.
If by the term 'generic' emphasis was placed on the name of the medicinal product, which is no longer that of the registered trademark but that of the active ingredient followed by that of the manufacturing company, with the term 'equivalent' the therapeutic equivalence to the originator drug is emphasised.
Two medicinal products are said to be bioequivalents if their bioavailability, i.e. the amount and speed with which the active substance is released and made available in the circulation, are equivalent.
Bioequivalence is demonstrated by bioavailability studies: if the two drugs being compared show similar bioavailability they are also, by definition, therapeutically equivalent and therapeutic equivalence studies are not necessary. Bioavailability, however, can only be assessed with reference to systemically administered drugs, whereas this parameter cannot be assessed in the case of topical drugs such as eye drops.
The granting by the Agenzia Italiana del Farmaco (AIFA) of a Marketing Authorisation (MA) for an equivalent medicine is based on the demonstration of the quality of the product and its bioequivalence to the Originator medicine (the latter condition only applies to systemic medicines).
The equivalent drug costs less than the originator because the investments made in research have already been recovered during the monopoly period granted by the patent. It is well known that in order to demonstrate the efficacy and therapeutic safety of a new drug, it is necessary to test it on hundreds, or even thousands, of subjects: such testing obviously takes time and implies high costs. The company that markets a generic medicine, on the other hand, is exempt from demonstrating therapeutic efficacy because, if the active ingredient reaches the same levels in the tissues as the originator medicine (i.e. if it is bioequivalent to it), it also has the same therapeutic efficacy. Demonstrating bioequivalence to a drug of known efficacy and safety requires much less time and cost, so the generic drug can be marketed at a lower price.
When the patent protection of a medicine reimbursed by the SSN expires and one or more equivalent medicines are authorised, the Italian Medicines Agency (AIFA) includes both the originator and the corresponding generics in a list, updated monthly, called transparency list. In this list, the originator medicine and corresponding generics are listed together, with the corresponding reference price. The reference price corresponds to the lowest price offered on the market for that medicine and is also the price reimbursed by the SSN. If a medicine appears on the transparency list and the doctor does not specify in the prescription that the medicine is "non-substitutable", the pharmacist must offer the patient the generic medicine offered at the reference price. If the doctor specifies "non substitutable" or the patient does not accept the substitution, any difference between the reference price and the retail price is borne by the patient.
On the basis of the above, one must then ask what is the role of the doctor? It is a relatively important role: often the patient, informed by the pharmacist of the possibility of substituting the generic drug for the original, asks his or her doctor to confirm or deny this choice.
In addition, there is now a consolidated trend towards the prescription of equivalent medicines as doctors become aware that, through their use, it is possible to achieve significant savings for the NHS, while continuing to guarantee adequate treatment and proper pharmaceutical care for citizens.
Based on your clinical experience, when should a patient undergo surgical treatment?
As well stated in the European guidelines, surgical treatment of glaucoma is indicated when medical therapy is not appropriate, not tolerated, not effective and/or not adequately performed by the patient and the glaucoma is uncontrolled with documented progressive damage or a high risk of disease progression.
However, no matter how much we try to schematise the indications for surgical therapy, the choice to undertake an intervention, in our clinical practice, is always very complex and conditioned by multiple factors that can be briefly exemplified as follows:
- the type of patient (age, 'compliance', personal needs, risk factors for glaucoma etc.);
- the type of glaucoma;
- the state of the optic nerve papilla and visual field (severity of glaucomatous damage);
- the pressure 'target' achieved and the type and number of drugs used;
- the intended pressure 'target' (to be assessed on a case-by-case basis);
- the safety of the planned surgery;
- the effectiveness of the planned surgery (visual recovery and achievement of the pressure 'target').
Given the multiplicity of elements that may influence the assessment of whether or not to proceed with a surgical treatment and, subsequently, the choice of the method to be performed, it is extremely difficult to provide a general outline that may assist in a decision that should therefore be made on a case-by-case basis.
Does trabeculectomy still represent the 'gold standard' in glaucoma surgery?
Today, trabeculectomy is still considered the procedure of first choice in glaucoma surgery, as it is the one that achieves satisfactory intraocular pressure control in the long term. This surgical method, which produces a 'protected fistula' between the anterior chamber and the subconjunctival space (reducing the ocular pressure), has been subject to many variations in the more than forty years since its invention, including the construction of the scleral flap (size, shape and thickness) and the conjunctival flap (fornix base or limbus), the sutures applied (number, releasable or non-releasable) and the use of antimetabolites to reduce scarring. The success rate (alone or with the addition of topical therapy) reported in the literature can be as high as 90% two years after surgery; however, there are significant differences in the definition of success among the various authors. In addition, it must be added that some patients require a repetition of the intervention and/or further medical therapy.
Finally, it is just as important to remember how the success of trabeculectomy is closely dependent on the creation of an efficient filtering draft, and how changes in the conjunctiva, induced by prolonged topical therapy, are one of the main factors that can affect the functioning of this structure.
Shall we briefly mention the scarring problems in filter surgery and the possible tricks that can be performed to limit them in order to improve surgical results?
As is well known, the scarring response that occurs at the level of the filtering draft represents the main cause of failure of trabeculectomy. This biological event obstructs the outflow of aqueous and consequently modifies the pressure 'target' to be achieved with the surgery.
The biological events that initiate the scar response are fibroblast activation (resulting from conjunctival, episcleral and scleral surgical incisions) and activation of coagulation factors and complement.
The substances that are commonly used intraoperatively to inhibit healing are the antimetabolites and the inserts. The former belong to that category of drugs that are able to prevent scarring following filtering surgery in order to promote surgical success. The most frequently used ones are 5-fluorouracil (5-FU) and mitomycin-C (MMC). 5-FU is an S-phase chemotherapy that inhibits cell replication by integrating into the DNA through fraudulent transformation. It is used at a concentration of 25-50 mg/ml undiluted solution. MMC is an anti-cancer antibiotic (isolated from the fermentation of Streptomyces Coespitosus), which is used at a concentration ranging from 0.1 to 0.5 mg/ml, for an application time of 2 to 4 minutes. In my clinical practice, I prefer to use MMC at a fixed concentration of 0.2 mg/ml, varying the application time depending on the case and the extent of inhibition of scarring processes required. It should be remembered that the use of antimetabolites as modulators of scarring in trabeculectomy is only based on clinical evidence, not on official approval (off-label drugs).
The inserts (Aqua Flow, SK Gel, T Flux, Healon Flow), some resorbable others not, are designed to act as conformers that, by maintaining spaces, prevent premature contact between the various tissues of the filter draft and consequently reduce fibrotic processes.
Finally, antimetabolites administered subconjunctivally and 'needling' of the draft are used to modulate healing in the post-operative period.
Is endophthalmitis a frequent complication in this type of surgery?
Endophthalmitis represents a complication, although fortunately not very frequent, nevertheless extremely serious, which can appear even months or years later: it can occur as an early (1%) or late (0.2%) complication. The filtering draughts that are most susceptible to infectious contamination are cystic draughts, with thin, translucent conjunctiva, with positive Seidel and in which we have used antimetabolites, so particular care must be taken in such circumstances.
To complete our interview, we would like your opinion on alternative surgical techniques to trabeculectomy such as Canaloplasty and Cy-pass?
Canaloplasty and Cy-pass implantation belong to the techniques of microinvasive glaucoma surgery (MIGS ).Canaloplasty makes use of a micro catheter that, when introduced into Schlemm's canal, dilates it, thus restoring the natural outflow pathways; in fact, by causing microfractures of the trabecular meshwork, increased metabolism of the extracellular matrix and an indirect action on the ciliary body leads to an increase in trabeculo-canalicular outflow.
The Cy-pass is a tubular 'device' that, implanted in the suprachoroidal space, increases the scleral uveal outflow. By exploiting the difference in pressure gradient between the anterior chamber and the suprachoroidal space, it causes the formation and maintenance of a cyclodiastasis.
Both techniques have the advantage that they do not depend for their operation on the creation of a filtering draft (a critical factor in trabeculectomy) and, in addition, they are surgical methods that induce little trauma for the patient and allow for rapid recovery.
However, I believe that MIGS methods still need to be further investigated, through randomised clinical trials, in order to highlight efficacy, long-term results, fields of use and cost/benefit ratios, also in comparison with trabeculectomy.
WHAT IS AN EQUIVALENT MEDICINE?
A drug is defined as equivalent to its originator if it has the same characteristics in terms of:
- active ingredient;
- dose;
- pharmaceutical form;
- route of administration;
- therapeutic indications and contraindications.
However, the excipients and/or preservatives may be different between the two products.
In addition, an equivalent drug must also be 'bioequivalent' to its originator, i.e. it must guarantee similar bioavailability (same quantitative and qualitative behaviour after administration), such that the same therapeutic and/or adverse effects are achieved.
Bioequivalence is demonstrated by bioavailability studies: if the two drugs being compared show similar bioavailability they are also, by definition, therapeutically equivalent (therapeutic equivalence studies are not necessary).
However, this rule only applies to systemically administered drugs and cannot be applied to topical drugs, such as eye drops, for which bioavailability is not an assessable parameter. In this case, bioequivalence is demonstrated by therapeutic equivalence studies.
Bioequivalence between equivalent drug and Originator must be demonstrated because a different composition of excipients and/or preservatives may alter the distribution of the active ingredient in the body, causing a change in bioavailability and thus therapeutic and/or adverse effects.
In the case of identical qualitative/quantitative compositions between the equivalent drug and the originator, there is obviously no need for any kind of study, as there is no possibility of a different distribution of the two drugs in the body.
Source: European Medicines Agency (EMA) - Food and Drug Administration (FDA)
Summing up:
BIOAVAILABILITY = similar distribution in the body, demonstrable by AUC, Cmax and Tmax curve comparison studies between equivalent drug and Originator
THERAPEUTIC EQUIVALENCE = overlapping clinical efficacy (similar therapeutic and/or adverse effects)
BIOEQUIVALENCE = similar distribution in the body (BIODISPONSIBILITY) such that the same therapeutic and/or adverse effects are obtained (THERAPEUTIC EQUIVALENCE)
Source: European Medicines Agency (EMA) - Food and Drug Administration (FDA)
Dr. Carmelo Chines
Direttore responsabile
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