Ocular Sodium Cromoglycate

Summary

Synopsis

Sodium cromoglycate stabilises mast cell membranes and prevents the release of histamine and other biochemical mediators. When topically applied to the eye before allergen exposure, ocular sodium cromoglycate¹ prevents many of the signs and symptoms associated with type I allergic reactions (which includes hayfever, acute allergic and chronic allergic conjunctivitis, and vernal keratoconjunctivitis) and giant papillary conjunctivitis.

Although difficulties exist in evaluating clinical trials in allergic eye disease, both open and controlled studies have shown ocular sodium cromoglycate to be very effective in relieving the subjective symptoms and clinical signs of the above ocular disorders. In addition, ocular sodium cromoglycate may decrease the need for supplementary oral antihistamines and, more importantly, the need for ocular corticosteroids, thus decreasing the incidence of steroid-induced ocular side effects. However, in severe cases and in instances of acute exacerbation of symptoms, the combined ocular application of sodium cromoglycate and corticosteroids may be very effective.

No systemic or severe adverse reactions have been attributed to ocular sodium cromoglycate, which is not surprising since systemic drug absorption from the eye is minimal. However, transient local stinging and burning have been reported.

Thus, although further studies in giant papillary conjunctivitis and comparative studies with corticosteroids in allergic conjunctivitis and vernal keratoconjunctivitis are needed to more clearly define the extent of benefits that may be obtained from ocular sodium cromoglycate, it is clear that the safety and efficacy of the drug in type I allergic eye diseases is such that it should be considered as a first-line agent when drug therapy of these disorders is indicated.

Pharmacodynamic Properties

Since the conjunctiva of the eye contains numerous inflammatory cells responsible for antigen elimination, phagocytosis and immunological memory of the individual, it is susceptible to a number of different types of allergic eye disease. The pharmacological effects of sodium cromoglycate have been ascribed to stabilisation of the mast cell membrane, which prevents the release of histamine and other biochemical mediators after the antigen (or offending allergen) has reacted with antibody at the cell surface. However, once these mediators have been released and symptoms have occurred, sodium cromoglycate is not effective except to prevent a reaction to the next exposure. Sodium cromoglycate has no direct vasoconstrictor, bronchodilator, antihistamine or anti-inflammatory activity.

Pharmacokinetic Studies

Sodium cromoglycate is effective only by topical administration due to its lipid insolubility. Only very low concentrations of sodium cromoglycate are systemically absorbed after ocular administration to man (about 0.03%) or rabbits (up to 0.02%). Sodium cromoglycate has been found to be detectable in aqueous humour of the rabbit eye for up to at least 7. hours but less than 24 hours after topical application. Systemically absorbed drug is excreted unchanged in the bile and urine.

Therapeutic Trials

Of the 4 major types of allergic eye conditions, ocular sodium cromoglycate is effective primarily on those of the IgE-mediated type I (atopic allergy or immediate hypersensitivity reaction) variety. These type I reactions include hay fever conjunctivitis and acute allergic conjunctivitis, which are caused by pollen and non-pollen allergens, respectively. Other type I reactions include chronic allergic conjunctivitis, which is used to describe the perennial form of allergic conjunctivitis, and vernal keratoconjunctivitis (potentially the most severe of the type I reactions). However, giant papillary conjunctivitis, which may be seen in users of contact lenses or associated with other foreign bodies, is unlikely to be mediated directly by IgE although ocular sodium cromoglycate has proven useful.

There are many difficulties in evaluating clinical trials of agents used to treat allergic eye diseases. Trials should be placebo-controlled and performed during the pollen season and be of ‘within-patient’ design. Since ocular sodium cromoglycate is essentially prophylactic, treatment should also ideally be initiated before any allergic symptoms have appeared. Importantly, since there has been no proven simple and reliable objective method of measuring the severity of symptoms of allergic eye diseases, reliance has been placed on patient subjective assessments of changes in the severity of their symptoms, using patient diary cards.

Open studies in allergic conjunctivitis have suggested ocular sodium cromoglycate 2 and 4% solutions are very effective in relieving the ocular signs and symptoms of hay fever conjunctivitis and acute allergic conjunctivitis within 7 days of the initiation of treatment 4 times daily. Moderate-to-excellent control of symptoms after 4 weeks of treatment have been judged to be achieved in as many as 96 and 92% of cases, according to patients and investigators, respectively.

The majority of controlled studies of ocular sodium cromoglycate 2 or 4% drops or ointment formulation in allergic eye diseases have been undertaken in patients with hay fever conjunctivitis. Ocular sodium cromoglycate provides significantly greater subjective symptom relief than placebo and patients have preferred the active drug over placebo in most cases. Ocular sodium cromoglycate also significantly decreases objective signs and the need for supplementary oral antihistamines. Ocular sodium cromoglycate 4% may be more effective than the 2% drops in controlling eye symptoms. The exact nature of the relationship, if any, between serum IgE concentrations and clinical effectiveness of ocular sodium cromoglycate has yet to be established.

The few studies comparing ocular sodium cromoglycate and ophthalmic corticosteroids in the treatment of hay fever conjunctivitis have shown that both drugs are effective in relieving symptoms, although steroids provide greater symptomatic relief, with no difference between the drugs with regard to patient preference. However, further studies involving larger numbers of patients are needed before definitive comparable efficacies can be established, although ocular sodium cromoglycate presents the patient with less risks of side effects with long term use than do ophthalmic corticosteroids.

In a small number of controlled trials in patients with chronic allergic conjunctivitis, ocular sodium cromoglycate has been shown to be significantly more effective than placebo and equivalent to dexamethasone 0.1% ophthalmic solutions. Again, however, more comparative studies of ocular sodium cromoglycate and corticosteroids are needed. Less satisfactory results have been seen in open trials of patients with chronic allergic conjunctivitis owing to the variable chronicity and severity of this disease entity; in these studies, ocular sodium cromoglycate should be given for longer periods (10 to 14 days) before evaluating therapy.

Ocular sodium cromoglycate 2 or 4% has been very effective in alleviating the subjective symptoms and objective signs of vernal keratoconjunctivitis. Open studies have shown that the drug may be effective as monotherapy in many cases. However, in patients with severe clinical symptoms the addition of corticosteroids, vasoconstrictors, antibiotics or mucolytics may be required. Ocular sodium cromoglycate is also significantly more effective than placebo in decreasing the many signs and symptoms of vernal keratoconjunctivitis.

There has been no correlation between the response to ocular sodium cromoglycate drops and serum IgE concentrations in patients with vernal keratoconjunctivitis. Ocular sodium cromoglycate 2% produces effects comparable to those produced by dexamethasone 0.1% ophthalmic solution, and decreases the need for corticosteroids in patients already receiving steroids. It may therefore reduce the incidence of steroid-associated side effects, including cataracts, infections and glaucoma. Ocular sodium cromoglycate and ocular corticosteroids may be used together with good effect in patients with either severe disease or acute symptom exacerbations.

In giant papillary conjunctivitis, ocular sodium cromoglycate 2 and 4% drops have produced symptom improvement reported within 2 to 30 days. However, further clinical studies involving larger numbers of patients are required to fully assess the effects of ocular sodium cromoglycate in this condition.

Side Effects

While no systemic or severe adverse reactions have been attributed to ocular sodium cromoglycate even after as long as 8 months of therapy, transient local stinging and burning have been reported in 13 to 77% of patients receiving the drug. However, these effects regress during continued treatment and may vary greatly according both to the individual and to the disease state. Stinging has been attributed to a preservative, 2-phenyl ethyl alcohol, used in some of the commercial formulations of ocularsodium cromoglycate, and there are indications that the omission of this preservative not only reduces the incidence of this side effect but also increases the efficacy of the drug by avoiding dilution with tears.

Dosage and Administration

Ocular sodium cromoglycate 2 and 4% drops should be given as 1 to 2 drops in each eye 4 to 6 times daily; the 4% sterile ophthalmic ointment should be applied to the lower eyelid 2 to 3 times daily, taking care to avoid direct contact between the eye and the tube nozzle. Ocular sodium cromoglycate should be stored in a cool place, protected from sunlight and discarded 4 weeks after the container has been opened.