Over-the-counter ophthalmic preparations

Medicinal products promoted, recommended or marketed for use as eye-drops or eye ointments are not available for general sale — they are all classified as pharmacy medicines.¹ Although ophthalmic complaints did not feature as one of the top 10 ailments for self-treatment recently described by Huw and Noyce,² there are a number of eye disorders which may be treated by over-the-counter (OTC) preparations.

Conjunctivitis is the first condition discussed in this article. This disorder is an inflammation of the mucous membrane that lines the eyelids and covers the anterior surface of the eye (excluding the cornea). Conjunctivitis may result from microbial infection or be allergic in origin. Both types are amenable to treatment with OTC preparations.

The OTC treatment of dry eye conditions is also discussed in this article. Table 1 describes the preparations available for OTC treatment of conjunctivitis, dry eye conditions and other minor eye irritations.

Infective conjunctivitis

Infective conjunctivitis can be bacterial, viral, chlamydial or fungal in origin. Staphylococcus species are the most common infecting bacteria in the United Kingdom, but others include streptococcus and haemophilus species.³ Viral infection may be caused by adenovirus and Herpes simplex virus. Chlamydial infection causes trachoma, which is the greatest cause of preventable blindness worldwide. Fungal conjunctivitis is rare in the UK, but may be encountered in rural areas.⁴

Infective conjunctivitis is characterised by a diffuse redness of the conjunctiva with a purulent (bacterial) or watery (viral) discharge. Viral infections are commonly associated with upper respiratory tract infections and swollen pre-auricular nodes.

Most cases of infective conjunctivitis are self-limiting but can be treated with the antimicrobial diamidines propamidine isethionate or dibromopropamidine isethionate. 

Antimicrobials

Historically, Golden Eye ointment contained mercuric oxide. This product was discontinued because of concerns about absorption and the adverse effects of inorganic mercury. In 1992, the brand name was used again when Golden Eye drops and ointment were reintroduced. These new products contain a diamidine as an antimicrobial and are an alternative to the well-established brand Brolene.

Brolene and Golden Eye drops contain the diamidine propamidine isethionate which has antibacterial, trypanocidal and fungicidal activity and is active against Staphylococcus aureus, Streptococcus pyogenes and certain other streptococci and clostridia.

The ointment preparations contain dibromopropamidine isethionate which has antibacterial and antifungal properties. It is active against pyogenic cocci, Staphylococcus aureus, and certain Gram-negative bacteria, including Escherichia coli, Proteus vulgaris and some strains of Pseudomonas aeruginosa. Fungi susceptible to the drug include Aspergillus niger and Candida albicans. The antibacterial activity of these diamidines is not reduced in the presence of organic matter, such as tissue fluids, pus and serum.

Both drops and ointment are licensed as “an anti-infective for use in local infections of the superficial structures of the eye due to micro-organisms sensitive to its action.” The products may be used in adults and children at a frequency of up to four times a day for the drops and once or twice a day for the ointment. 

If no improvement is seen within two days, medical opinion should be sought.

The aim of antimicrobial therapy is to achieve a concentration of the antimicrobial agent at the site of infection high enough to kill or stop the growth of the infecting organism. It is doubtful that the licensed frequency of administration will achieve this, and Edwards and Stillman suggest hourly use of propamidine isethionate eye-drops.⁵ 

Combining this intensive therapy during the day with the longer-acting eye ointment at night will increase the possibility of resolving the infection. 

Propamidine isethionate, in combination with a wide range of agents, has been used in the treatment of Acanthamoeba keratitis.⁶ This use of the product is outside its current product licence.

Allergic conjunctivitis

Several types of hypersensitivity reactions in the eye are recognised. Those amenable to treatment with OTC medicines are of the immediate hypersensitivity type and include acute allergic conjunctivitis, seasonal or hay fever conjunctivitis and vernal keratoconjunctivitis.

In all cases, the disease process is thought to be initiated by allergens combining with immunoglobulin E which is bound to conjunctival mast cells. This interaction causes mast cell degranulation leading to the release of numerous chemical mediators, such as histamine.⁷ These mediators trigger the inflammatory cascade, resulting in vasodilatation, increased vascular permeability and oedema and give rise to the classical symptoms of allergic conjunctivitis (see Panel).

Preparations used to treat allergic conjunctivitis contain mast cell stabilisers, antihistamines, sympathomimetics and astringents.

Mast cell stabilisers 

Two mast cell stabilisers may be sold in the pharmacy for the prevention, relief and treatment of seasonal and perennial allergic conjunctivitis – sodium cromoglicate 2 per cent in the form of aqueous eye-drops in packs of up to 10ml, and nedocromil sodium in a container of not more than 3ml with a maximum strength of 2 per cent. Sodium cromoglicate may also be sold in the form of a 4 per cent eye ointment in packs of up to 5g for the treatment of acute seasonal allergic conjunctivitis.¹ However, at the time of writing this article, there are no commercially-available preparations of sodium cromoglicate eye ointment; the prescription only product, Opticrom, was discontinued in 1998. As yet, no company has received a pharmacy licence for nedocromil. 

Sodium cromoglicate eye-drops may be used in adults and children at a frequency of four times a day. As the drug has no intrinsic vasoconstrictor or antihistaminic activity, it should be used regularly to prevent symptoms. The drops have been shown to be superior to placebo in suppressing eye symptoms in seasonal allergic conjunctivitis. In a double-blind, placebo-controlled trial of sodium cromoglicate in 43 patients,⁸ both patients and physicians assessed sodium cromoglicate to be more effective than placebo. Another trial⁹ showed that there was a trend for associated nasal symptoms and the requirement for nasal beclomethasone to be lower in the treatment group. 

In a randomised trial involving 62 adults with ragweed pollen conjunctivitis, subjects received sodium cromoglicate regularly four times a day or when needed, up to four times daily. The researchers concluded that there might be some additional therapeutic benefit from using sodium cromoglicate regularly throughout the ragweed pollen season.¹⁰ Although diary symptoms were similar in the two treatment groups, quality of life was better in the regular treatment group and the “when needed” group required more terfenadine for uncontrolled eye symptoms.

Topical sodium cromoglicate has been compared with oral antihistamines and found to be as effective as terfenadine¹¹ and more effective and faster in relieving symptoms than astemizole.¹²

In vernal keratoconjunctivitis, sodium cromoglicate eye-drops were found to be as effective as Decadron (dexamethasone sodium phosphate) and superior to Antistin-Privine (antazoline sulphate and naphazoline nitrate).¹³

If nedocromil sodium becomes available as an OTC product, it has a number of advantages over sodium cromoglicate. Twice daily nedocromil sodium has been shown to be as effective as sodium cromoglicate four times daily.¹⁴ Nedocromil sodium is useful in patients with perennial allergic conjunctivitis unresponsive to sodium cromoglicate, and it produces a more rapid and marked improvement in symptoms of vernal keratoconjunctivitis than sodium cromoglicate.¹⁵

Antihistamines 

Histamine released from mast cells causes dilatation of the small precapillary blood vessels and constriction of the larger venules, resulting in passive capillary dilatation. In addition, histamine causes oedema by constricting cells of the small venules, thus exposing the basement membrane and allowing plasma to pass into the extracellular space. In the eye, histamine release produces characteristic symptoms of ocular allergy: itching, redness, tearing and chemosis (build-up of fluid under the conjunctiva).¹⁶

Oral H1-antagonists, such as astemizole and loratadine, are effective and generally well tolerated in seasonal allergic conjunctivitis. However, although these drugs are well absorbed after oral administration, it may take several hours to achieve maximum antihistaminic effects.¹⁷ With topical treatment, maximum therapeutic effects are achieved rapidly because the drug is applied directly to the affected organ. In addition, the risk of systemic adverse effects will be considerably reduced. There are two topical antihistamines available OTC: antazoline contained in Otrivine-Antistin, in combination with the sympathomimetic xylometazoline, and the newer, more potent drug, levocabastine. 

Antazoline 

Antazoline was introduced over 50 years ago and a paper published in 1948¹⁸ reported that an ophthalmic solution of the drug proved of definite therapeutic value in 50 cases of ocular allergy.

The use of combination drops in allergic conjunctivitis is widespread and well accepted. Studies of such preparations have shown that they are useful in controlling symptoms and well tolerated by patients.¹⁹ Otrivine-Antisitin eye-drops are licensed for use in adults and children over five years at a frequency of two to three times daily.

Levocabastine 

In 1998, this new H1-antagonist, available on prescription as Livostin, became classified as a pharmacy medicine in the form of aqueous eye-drops for the symptomatic treatment of seasonal allergic conjunctivitis in a container of not more than 4ml. The OTC version of the drops, Livostin Direct, was launched in March, 1999.

Levocabastine has been specifically developed for ocular and nasal administration. Its potency is significantly greater than that of antazoline.²⁰ It does not display anticholinergic or antiserotonin activity^21,22 and repeated instillations do not cause any sedative effects.²³ Levocabastine has a rapid onset of action, providing relief from symptoms of histamine-induced conjunctivitis within 10 minutes of instillation²⁴ and has a sufficiently long duration of action to permit a convenient twice daily dosage.

In a comparison between levocabastine and naphazoline/antazoline eye-drops in seasonal allergic rhinoconjunctivitis, significantly more patients using levocabastine rated it excellent. Patients using levocabastine also experienced fewer side effects.²⁵

A number of trials have compared levocabastine twice daily with sodium cromoglicate four times a day in the treatment of seasonal allergic conjunctivitis. Levocabastine was shown to be equally effective^26-28 or more effective²⁹ than cromoglicate. Moreover, levocabastine has been shown to be significantly more effective than sodium cromoglicate in inhibiting itching, redness, eyelid swelling, chemosis and tearing in an allergen challenge model of allergic conjunctivitis, and it inhibits the signs and symptoms of allergic conjunctivitis after a single instillation.³⁰ 

However, in one study of children between six and 16 years of age,³¹ in which levocabastine or sodium cromoglicate were administered in addition to regular oral terfenadine, the sodium cromoglicate group experienced slightly fewer eye symptoms throughout the trial.

Several studies comparing topical levocabastine with oral antihistamines have shown that the topical drug is as effective as,^32-34 or more effective than,^35,36 the systemic antihistamine in relieving ocular symptoms. All these studies report that levocabastine was well tolerated. A significantly faster relief of ocular symptoms was seen with levocabastine eye-drops than with oral cetirizine in a study reported by Drouin et al.³⁷ In a review of levocabastine, Bahmer concludes that the topical drug is an attractive alternative to oral antihistamines as a first-line therapy for the treatment of seasonal allergic rhinoconjunctivitis.³⁶

Levocabastine has also been shown to be effective and well tolerated in the treatment of vernal conjunctivitis,^38,39 seasonal allergic rhinoconjunctivitis,^40,41 and allergic conjunctivitis from house dust mite in a variety of patient groups, including children under 12 years of age.⁴² However, these indications are currently outside the licensed indications. The OTC preparation is only licensed for the symptomatic treatment of seasonal allergic conjunctivitis in adults and children over 12 years. In addition, although several studies have shown efficacy and lack of tachyphylaxis over periods of up to 16 weeks,⁴³ the use of Livostin Direct eye-drops is currently limited to a total of four weeks in any one year. 

Sympathomimetics 

Three sympathomimetic drugs are available in OTC remedies “for the temporary relief of redness of the eye due to minor eye irritation” or “as a decongestant for relief of minor eye irritation.” Following topical application to the eye, constriction of conjunctival blood vessels occurs at concentrations that generally do not cause pupillary dilatation. These agents provide only palliative therapy, since they have no effect on the conjunctival response to antigen.¹⁶

Phenylephrine 

At the concentration used for ocular decongestion, 0.12 per cent, phenylephrine causes vasoconstriction by direct stimulation of a-receptors on conjunctival vasculature, causing a decrease in conjunctival hyperaemia and oedema. Dilatation of the pupil can occasionally occur, particularly if the corneal epithelium is damaged or diseased.⁴⁴ Chronic use can cause a rebound of conjunctival congestion resulting in conjunctivitis medicamentosa.⁴⁵ 

Although phenylephrine is also classified as a pharmacy medicine in the higher strengths of 2.5 per cent and 10 per cent, and available as Minims phenylephrine hydrochloride in these strengths, these preparations are licensed not as decongestants but as mydriatics. Over-the-counter sale of both of these higher strength products should only be made if the patient is using the drug under the direction of an ophthalmologist.

Naphazoline 

Naphazoline is included in OTC eye-drops at a concentration of between 0.01 to 0.012 per cent, either alone or in combination with an astringent. The majority of clinical trials comparing naphazoline with other decongestants have used concentrations of the drug higher than those available in the UK.¹⁶ However, one study compared naphazoline 0.012 per cent with phenylephrine 0.12 per cent and tetrahydrozoline 0.05 per cent in 40 healthy adults.⁴⁶ None of the drugs caused significant changes in pupil size or anterior chamber depth, however; naphazoline produced a somewhat higher average intraocular pressure than the control.

The use of naphazoline in products marketed as cosmetic products for “bright sparkling eyes” and “clearer whites” should be limited to occasional use, as the vasoconstriction produced by naphazoline will mask diagnostic signs of eye disease.

Xylometazoline 

The effect of xylometazoline is similar to naphazoline but its action is somewhat less intense and less prolonged and the drug is better tolerated by some patients.⁴⁷ 

Hurwitz states that it is of greatest value in surface ocular conditions with congestion of the conjunctiva lining the eyeball and eyelids and its attendant symptoms, ie, tearing, photophobia, blepharospasm and smarting. The vasoconstrictor action of xylometazoline starts immediately after ocular instillation and continues for two to four hours. It is well tolerated with a minimal burning sensation.⁴⁸ The author describes 48 cases and comments that the drug is “strikingly effective in relieving epiphora [watering], photophobia, conjunctival congestion, smarting and foreign body sensation, with 70 per cent of the patients being symptomatically relieved.” Untoward symptoms consisted of mild, burning sensation and an occasional blurring of vision. No damage or irritation to the conjunctiva or cornea was seen. 

In the UK, xylometazoline is only available at a concentration of 0.05 per cent in combination with the antihistamine antazoline (see above) as Otrivine-Antistin. Trew et al⁴⁹ studied 16 healthy subjects and recorded the sympathomimetic responses to evaluate any possible risks associated with the use of Otrivine-Antistin, which is contrainidicated in narrow angle glaucoma. The drops produced mild sympathomimetic responses in the eye: small, though statistically significant, changes in pupil diameter, palpebral height and conjunctival vessel diameter compared with the placebo vehicle. Importantly, the mydriatic response was too small to be of clinical significance or to impose any risk of pupil block or irido-corneal angle closure and thus of acute glaucoma, even in susceptible subjects. The eye-drops had no effect on corneal sensitivity or on intraocular pressure and produced some mild and transient irritation in some subjects, consistent with clinical experience. The authors concluded that Otrivine-Antistin produces mild sympathomimetic responses in the eye but that, in its use as a decongestant, these are harmless and impose no risk to the subject.

Adrenaline 

Adrenaline eye-drops, neutral BPC are also listed as a pharmacy medicine. However, as both commercially available preparations of this formulation, Eppy and Simplene, used for the treatment of primary open angle glaucoma, are classified as prescription only medicines, a request for a sale would be unlikely.

Astringents 

Preparations containing the astringents distilled witch hazel and zinc sulphate are indicated for the relief of minor eye irritations. Astringents are locally acting drugs that precipitate proteins. These preparations are so poorly penetrative that only the cell surface is affected, resulting in greatly reduced cell permeability and thus watering.¹⁹

Distilled witch hazel is employed at a concentration of 12.5 to 13 per cent v/v in products indicated for the temporary relief of redness of the eye due to minor eye irritations. Zinc sulphate, which also has a mild antiseptic properties, is employed at 0.25 per cent. There is little information in the literature on the efficacy of such preparations. In a study on eye irritation in hay fever, Clark et al reported that 71 per cent of patients derived benefit from Optrex eye lotion used three times daily.⁵⁰ Another study, published in a French journal, reported a very good or excellent result in 78 per cent of cases after the addition of zinc sulphate to a topical antihistamine preparation.⁵¹ However, most authors are dismissive of the benefits of astringents. They have been described as of “doubtful value” and best recommended where no specific syndrome exists, for example, in cases where a patient complains of “tired eyes” but has no significant conjunctivitis.^5,52

Severe cases of infective conjunctivitis should be referred for treatment with antibiotic therapy and cases of allergic conjunctivitis that are non-responsive to OTC medicines can be prescribed alternative mast cell stabilisers or antihistamines by the general practitioner.

Dry eye conditions

The term “dry eye” refers to a group of ocular disorders related to deficiencies in the quantity and/or quality of the tear film. Dry eye may result from dysfunction or absence of the meibomian glands which secrete the lipid component of the tears, deficiency of the basal mucin layer of the tears or aqueous tear film deficiency. A decreased blink rate or defective spreading of the tear film may also result in a dry eye.

Dry eye is most frequently encountered in menopausal and postmenopausal women, but can affect individuals at any age and of either sex. Non-pharmacological measures, such as the use of room humidifiers, may offer the patient a degree of relief but the mainstay of pharmacological treatment is artificial tears, many of which are available OTC.⁵³

Artificial tears 

Preparations containing substituted cellulose ethers of high viscosity, such as methylcellulose, used in ophthalmology since 1945,⁵⁴ are useful in aqueous tear deficiency. Other substituted cellulose ethers, particularly hydroxyethylcellulose and hydroxypropylmethylcellulose (hypromellose), are somewhat less viscous than methylcellulose but possess cohesive (film-forming) and emollient properties equal or superior to those of methylcellulose. However, although viscous agents enhance the ocular retention time of tear substitutes, high viscosity itself does not provide relief for all dry eye conditions.⁵⁵ 

Other less viscous hydrophilic substances, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (povidone or PVP), have been included as the polymeric ingredients of many artificial tear formulations.

The tears of patients with dry eyes due to aqueous deficiency have been shown to have a higher osmolarity than normal subjects,⁵⁶ a factor which may be responsible for the ocular surface disease in this condition.⁵⁷ In such patients, hypotonic solutions such as polyvinyl alcohol 1 per cent with an osmolarity of 150 mOsm/L have been shown to be superior to an isotonic solution of 300 mOsm/L in providing symptom relief.^58,59

Ingredients such as PVA and PVP impart good wetting properties to the corneal surface and are therefore useful in patients with mucin deficiency. PVA at a concentration of 1.4 per cent has surface tension equivalent to normal tears and optimal wetting characteristics. All these preparations have been shown to prolong tear break up time, a measure of the stability of the tear film.^60,61

Patients with mild dry eye may benefit from instillation of one of these artificial tear drops up to four times a day. However, in moderate to severe cases, these preparations need to be instilled more frequently. 

To overcome this problem, preparations containing a longer-acting polymer, polyacrylic acid, also known as carbomer 940, have been introduced. Such preparations have a much longer retention time in the eye and symptom relief is obtained with significantly fewer instillations.^62,63 

Fewer instillations of an artificial tear preparation will also expose the patient to less preservative load, an important factor because benzalkonium chloride, the preservative most frequently used in artificial tear preparations has been shown to be toxic to the corneal endothelium.⁶⁴ Göbbels and Spitznas⁶⁵ have shown a decrease in epithelial permeability in patients treated with unpreserved polyvinylpyrrolidone 2 per cent, while those receiving the same preparation preserved with benzalkonium chloride 0.005 per cent showed an increase in permeability. The authors suggest that, in dry eyes, treatment with unpreserved artificial tears may lead to an objective improvement in corneal surface disease, with this effect being counteracted by preservation of tear substitutes with benzalkonium chloride.

An extensive range of preservative-free artificial tear preparations is now available. Although Göbbels and Spitznas’s findings would recommend their use in all patients, it is unlikely that patients purchasing dry eye products OTC would wish to bear the cost of unit dose preparations unless they fall into the category of patients in whom preserved eye-drops are contraindicated. These include patients allergic to, or intolerant of, preservative and patients who wear soft contact lenses.

Preparations vary in composition and viscosity and as patients with dry eye are very sensitive to such differences, the patient may need to try a range of preparations before settling upon one which suits them. 

Lubricating ointments 

Ophthalmic lubricating ointments contain white soft paraffin, lanolin and liquid paraffin. These preparations melt at the temperature of the ocular tissue and are retained longer than other ophthalmic vehicles.⁶⁶ They are not generally recommended as tear substitutes during the day as vision is blurred after instillation. They are, however, a useful adjunct to artificial tears if used at bedtime. 

Lack of response to OTC preparations in patients with dry eye conditions warrants referral because ophthalmic examination may reveal underlying pathology amenable to medical or surgical correction.

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