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Glaucoma medication: problems, products and predictions--Part 1.

The first in a series of two articles, ophthalmic pharmacist Lucy Titcomb discusses recent changes to medication for the management of glaucoma. She considers the potential for new therapeutic agents in the future, including novel vehicles for drug delivery emerging in the marketplace, bringing optometrists up to date on these developments.

Course code: C-36837 | Deadline: July 18, 2014

Learning objectives

To be able to explain to patients about potential adverse effects of glaucoma medication (Group 1.2.3)

To be able to recognise adverse reactions to glaucoma medication (6.1.15) Learning objectives

To be able to explain to patients about potential adverse effects of glaucoma medication (Group 1.2.3)

To be able to understand the medical treatment of glaucoma (Group 8.1.3)

Learning objectives

To be able to understand the pharmecological approach to glaucoma treatment (Group 1.1.2)

To be able to explain the nature of glaucoma treatment to patients (Group 3.1.11)

To be able to keep up to date with advances in glaucoma treatment and emerging safety concerns related to prescribing (Group 4.1.5)

Introduction

Over the past four years there have been a number of discontinuations and interruptions to the supply of topical ophthalmic products used in the treatment of glaucoma in the UK market. However, there have been several new products introduced. Ophthalmologists and optometrists have also had to deal with the discontinuation of products used in tonometry.

Discontinuations

In 2011, Alcon discontinued its once-daily pilocarpine 4% preparation, Pilogel. Patients using this product required a review by an ophthalmologist to determine the most appropriate alternative. While inconvenient for patients who had to be switched to three-to-four times daily instillation of eye drops, review of patients using the oldest drug in the glaucoma armamentarium may have been beneficial for many.

In the following year, another once-daily preparation, the Novartis product Nyogel was discontinued. This product contained the lowest dose of a beta-blocker available as an eye drop (timolol 0.1%) and was useful for the treatment of glaucoma in pregnant and breast-feeding women in whom low dose products are preferred. Health care professionals had to consider the pros and cons of changing to timolol 0.25% or the more costly preservative-free timolol 1mg/g preparation, Tiopex from Spectrum Thea.

In March 2013, Bausch & Lomb shocked the world of ophthalmology by announcing the discontinuation of Fluorets, fluorescein ophthalmic strips 1mg. Although there are other fluorescein strips on the market (Bioglo, Omnifluoro), Fluorets was the only product licensed as a medicine as required by the Medicines and Healthcare Products Regulatory Agency (MHRA) for diagnostic ophthalmic strips used in the UK. In the absence of an alternative licensed medicinal product, the MHRA has clarified the position on the use of alternative products:

* Fluorescein strips intended for diagnostic purposes are regarded as medicinal products because they are in vivo diagnostic agents. Therefore, they need a marketing authorisation under the requirements of the medicines legislation if they are intended for diagnostic purposes

* These strips, if intended and marketed only for the fitting of contact lenses, can be CE marked as medical devices, but the manufacturer should not describe such products as suitable for diagnostic purposes

* The regulatory classification of this category of products is currently being considered at European level

* However, to avoid shortage of supply, the MHRA will not take formal regulatory action to stop these products with a CE mark being used for diagnostic purposes until a decision about these products has been made at European level

* There are no restrictions on the sale and supply of medical devices, therefore, practitioners can use a product which has been CE marked as a medical device.

Bausch & Lomb also announced recently the discontinuation of another commonly used drug, Minims proxymetacaine hydrochloride with fluorescein. This product was a popular choice for many when undertaking applanation tonometry and optometrists and ophthalmologists now have to consider alternatives. Users of these products have a choice of using a local anaesthetic and a CE marked fluorescein strip or the Minims combination of lidocaine with fluorescein which is less well tolerated than the more frequently used proxymetacaine with fluorescein. (1)

Interruptions to supply

Shortages of preservative-free products manufactured by MSD plagued those involved in the care of glaucoma patients from 2010 to 2013. The company explained that this was due to an increase in worldwide demand for ophthalmic products in the preservative-free range. Supplies of timolol (Timoptol), dorzolamide (Trusopt) and dorzolamide with timolol (Cosopt) preservative-free products were affected but MSD's preservative-free prostaglandin analogue tafluprost (Saflutan) was not, owing to a different source of manufacture (Santen Pharmaceutical).

Although prescribers could turn to alternative preservative-free beta-blockers such as betaxolol (Betoptic), levobunolol (Betagan) or, following its launch in October 2011, the low-strength timolol preservative-free gel Tiopex for patients on Timoptol preservative-free, there was no alternative for patients on the other products, necessitating a review of treatment.

Patients stabilised on pilocarpine encountered difficulties in obtaining multi-dose eye drops in 2013 and had to be prescribed alternative strengths, or when supplies of these were exhausted, Minims pilocarpine nitrate.

Finally, there have also been problems with supplies of Alcon's products brinzolamide (Azopt), travoprost (Travatan) and travoprost with timolol (Duotrav). A weak Pound and strong Euro has increased the demand for UK medicines and shortages occur because these medicines are being exported to other European countries. Unfortunately, it is not possible to prevent the export of UK medicines, as this would contravene European trade laws. Despite the manufacturer putting up to 25,000 units per month more into the UK market than the UK patient demand dictates, shortages of these three products are still being reported. (2)

These shortages are of major concern to patients stabilised on glaucoma medication. Of 249 calls received by the International Glaucoma Association's Sightline in July to August 2012, 11% related to shortages of eye drops. Fortunately, resolution of some of these issues has led to a reduced number of such calls in the same period last year. In July to August 2013, 4% of 389 calls concerned this topic.

A new problem

While problems with the supply of MSD products were resolved in July 2013, patients receiving the reintroduced supplies of Cosopt preservative-free started to complain about the new delivery system employed for this product.

Between July and December 2013, 69 complaints had been passed to the manufacturer or the MHRA. The product supplied from July 2013 did not have a tapered nozzle so when the top was snapped off the nozzle was attached to two plastic lugs (see Figure 1, p49). If the patient did not present this dropper vial to the eye in the correct orientation they could easily scratch their eye with one of the plastic lugs resulting in a corneal abrasion.

The MHRA advised that patients using the product may experience problems administering their eye drops, and could benefit from additional education in the safe self-administration of eye drops. They encouraged the reporting of any problems via the Yellow Card Scheme. (3) Nevertheless, there were alternatives for prescribers. MSD's unit dose vials of the single agents, dorzolamide and timolol remained available in the original delivery system. This, however, involved administering two drops rather than one at greater expense for NHS prescribers and for patients paying privately for their prescriptions. Fortunately, Teva launched a licensed generic, preservative-free dorzolamide and timolol eye drop in April 2013.

In February 2014, MSD introduced a new design of the Cosopt preservative-free container, still with lugs but at a further distance from the tip (see Figure 2). The delivery system still retains some of the undesirable features and needs to be administered in a particular orientation and, therefore, is seen as an interim measure. Residual stocks of the design which had caused corneal abrasions were withdrawn on February 17, 2014. (4,5)

New products

2010 and 2011 saw the introduction of a number of new formulations of prostanoid glaucoma agents. In February 2010, Allergan introduced a new lower strength of their prostamide bimatoprost. In addition to the existing product, the original Lumigan, which contains bimatoprost 0.03% and benzalkonium chloride 0.005%, prescribers were offered a new Lumigan containing bimatoprost 0.01% but with a higher concentration of benzalkonium chloride, 0.02%. With the increased concentration of preservative necessary to enhance drug penetration, reseachers found that bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering intraocular pressure (IOP) throughout 12 months of treatment. (6) Although a more costly preparation, patients experiencing adverse reactions with the 0.03% strength may tolerate the new product better and persist with treatment. (7,8) A practical problem is the lack of differentiation in brand name for the two products and prescribers must remember to include the strength required on prescriptions for this drug. In the absence of strength, pharmacists will dispense the lower strength.

Later that year Alcon changed the formulation of their prostaglandin analogue, travoprost (Travatan) and in early 2011 that of travoprost with timolol (Duotrav) replacing the preservative benzalkonium chloride with Polyquad. Although this preservative has been used in contact lens solutions and ocular lubricants for some time, the new Travatan was the first eye drop classed as a medicine to be preserved with Polyquad. Studies have shown that the Polyquad-containing formulation of travoprost is as effective as that containing benzalkonium chloride. (9) Further, there is less damage to corneal epithelial cells with the new formulation following in vitro experiments. (10,11) These changes may have been introduced to increase the use of these branded products prior to the introduction of generic versions of latanoprost in January 2012, a topic for discussion in Part 2 of this series.

Last year saw the launch of three new preservative-free glaucoma preparations, bimatoprost preservative-free 0.03% (Lumigan 0.3mg/mL eye drops, solution, in single-dose container); latanoprost preservative-free 0.005% (Monopost) and bimatoprost 0.03% with timolol 0.5% preservative-free (Ganfort 0.3mg/mL + 5mg/ mL eye drops, solution, in single-dose container).

Bimatoprost preservative-free, launched in January 2013, is only available at the higher strength because, as stated earlier, benzalkonium chloride is a necessary part of the formulation at the lower strength. The formulation of bimatoprost preservative-free is identical to that of the original product except for the omission of benzalkonium chloride. In a study published seven months after the launch of the product, Day et al demonstrated non-inferiority to the preserved product but there was no significant difference in the incidence of adverse events. (12) Published studies comparing the efficacy and tolerability of bimatoprost with timolol preservative-free launched in September 2013 with the preserved product are still awaited.

In contrast, the formulation of latanoprost preservative-free (Monopost) launched in March 2013 by Spectrum Thea, is quite different to that of the preserved product (see Table 1, p49) but prescribers had the reassurance of a paper published shortly before launch demonstrating equivalence in efficacy and lack of toxicity of the new formulation to corneal epithelial cells. (13) An adjusted indirect comparison meta-analysis of randomised clinical trials of latanoprost preservative-free and the preserved prostaglandin analogues travoprost 0.004%, bimatoprost 0.03% and bimatoprost 0.01% demonstrated that the new product was not inferior to the other drugs in terms of efficacy on IOP and that the risk of hyperaemia was significantly lower with latanoprost preservative-free than with the preserved formulations. (14)

Products under investigation

Products used in the treatment of glaucoma, which may be launched in the UK in the near future include:

* The prostaglandin analogue unoprostone isopropyl

* New combinations of existing drugs

* New chemical entities

* New delivery systems for existing drugs.

Unoprostone isopropyl

Unoprostone, used as the isopropyl ester for the treatment of glaucoma and ocular hypertension, is like latanoprost, a synthetic analogue of dinoprost (prostaglandin F2a). Unoprostone is already available as Rescula (Sucampo Pharmaceuticals) in the United States, Japan and several South American countries. It is said to have a lower incidence of eyelid bristles than the other prostanoids but has the disadvantage of requiring twice-daily administration. (15)

New combinations of existing drugs

Alcon's Simbrinza is the first combination therapy for glaucoma which does not contain timolol. The product, which was launched in the United States in April 2013 is a combination of brinzolamide and brimonidine. Simbrinza has now been approved in Europe following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) (16) and and a UK launch awaits authorisation from the MHRA. Three and six month studies have provided evidence that the fixed combination of brinzolamide 1%, and brimonidine 0.2%, can safely and effectively lower IOP in patients with open-angle glaucoma or ocular hypertension, showing significantly superior IOP-lowering activity compared with either brinzolamide or brimonidine monotherapy while providing a safety profile consistent with that of its individual components. (17,18)

New chemical entities

Many other drugs with potential for use in glaucoma are under investigation including:

* Adenosine receptor analogues (Inotek) --Trabodenoson (previously called INO8875 and PJ-875)

* NO-donating moieties in combination (Bausch & Lomb)--latanoprostene bunod (previously called BOL-303259-X and NCX-116)

* Rho-kinase inhibitors (Aerie)--AR-12286; PG 286 (AR-12286 + travoprost)

* Rho-kinase inhibitors + norepinephrine transporter inhibitor (Aerie)--AR-13324; PG 324 (AR-13324 + latanoprost)

The reader is referred to an excellent review by Lee and Goldberg (2011) and to the clinical trials website for further information. (19,20)

New delivery systems for existing drugs

Many patients have difficulty in self-administration of eye drops while others just forget to use their medication. Patients with glaucoma and ocular hypertension are, therefore, likely to benefit from the introduction of a biodegradable extended release latanoprost subconjunctival insert or a slow release punctal plug delivery system for long-term drug delivery of bimatoprost. (20,21)

Non-ophthalmic applications

Finally, there are two non-ophthalmic uses of drugs used in the treatment of glaucoma, one product launched recently and the other in the pipeline. The sympathomimetic brimonidine at a concentration of 0.33% in a dermatological gel formulation was launched as Mirvaso in April 2014. Moore and colleagues described once-daily topical brimonidine gel 0.5% as safe and consistently effective for the long-term treatment of moderate to severe erythema of rosacea, even in the presence of concomitant therapies for the inflammatory lesions of rosacea. (22)1

Optometrists will be aware of thickening and lengthening of the eyelashes and hypertrichosis as side effects of the prostanoid group of drugs. Allergan have turned this into an advantage by launching bimatoprost as a cosmetic preparation in the United States where the 0.03% strength of the drug is available as Latisse where it is also being investigated as therapy for hypotrichosis of the eyebrows. (23,24)

Conclusion

The landscape for medical glaucoma treatment is ever changing with the continued efforts of the pharmaceutical industry to develop drugs with maximal efficacy and minimal adverse effects. It is important for practitioners to keep up to date with this rapidly evolving field.

Reflective learning

Having completed this CET exam, consider whether you feel more confident in your clinical skills--how will you change the way you practice? How will you use this information to improve your work for patient benefit?

Exam questions

Under the enhanced CET rules of the GOC, MCQs for this exam appear online at www.optometry.co.uk/cet/exams. Please complete online by midnight on July 18, 2014. You will be unable to submit exams after this date. Answers will be published on www.optometry.co.uk/cet/exam-archive and CET points will be uploaded to the GOC every two weeks. You will then need to log into your CET portfolio by clicking on 'MyGOC' on the GOC website (www.optical.org) to confirm your points.

References

Visit www.optometry.co.uk/ clinical, click on the article title and then on 'references' to download.

Lucy Titcomb FRPharmS MCPP

Lucy Titcomb is the lead ophthalmic pharmacist at Birmingham and Midland Eye Centre and a visiting lecturer at Aston University and City Hospital, London. She is a founder member and past chairman of the UK Ophthalmic Pharmacy Group and has authored numerous publications in the field of ophthalmic pharmacy.

Table 1 Ingredients of latanoprost multidose and preservative-free
formulations

Multidose latanoprost             Preservative-free latanoprost
                                  (Monopost--Spectrum Thea)

* Latanoprost 0.005%              * Latanoprost 0.005%
* Benzalkonium chloride 0.02%     * Macrogolglycerol
                                    hydroxystearate 40
* Sodium dihydrogen phosphate     * Sorbitol
  dihydrate/monohydrate
* Disodium phosphate              * Carbomer 974 P
  dodecahydrate/Anhydrous         * Macrogol 4000
  disodium phosphate/Disodium
  hydrogen phosphate anhydrous
* Sodium chloride                 * Disodium edetate
* [+ or -] Sodium hydroxide or    * Sodium hydroxide
  hydrochloric acid to adjust       (for pH adjustment)
  pH
* Water for                       * Water for injections
  injections/Purified water
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Article Details
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Title Annotation:1 CET POINT
Author:Titcomb, Lucy
Publication:Optometry Today
Geographic Code:4EUUK
Date:Jun 20, 2014
Words:2733
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