Data Sheet

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DIPOQUIN

Dipivefrine hydrochloride Eye Drops 0.1%

Presentation

Eye Drops: 0.1% w/v dipivefrine hydrochloride (an ester and prodrug of the adrenergic agonist adrenaline), 0.005% w/v benzalkonium chloride as preservative; in a clear, colourless to pale yellow, sterile aqueous solution.

Uses

Actions

Optic nerve head damage and visual field loss are the result of sustained elevated intraocular pressure and poor ocular perfusion. The adrenaline liberated from dipivefrine hydrochloride appears to exert its action by decreasing aqueous production and enhancing outflow facility. The onset of action with one drop of dipivefrine hydrochloride (0.1%) occurs approximately 30 minutes after treatment, with maximum effect seen at approximately one hour.

DIPOQUIN Eye Drops 0.1% are effective alone in reducing intraocular pressure but are most useful when used in conjunction with ophthalmic β-blockers (e.g. betaxolol hydrochloride).

Pharmacokinetics

Dipivefrine hydrochloride is a member of a class of drugs known as prodrugs. Routinely prodrugs are not themselves pharmacologically active, requiring biotransformation to the parent compound before a therapeutic action occurs. The modifications of a parent compound to a prodrug are made to enhance absorption, decrease side effects and enhance stability and comfort.

Dipivefrine hydrochloride, formed by the diesterification of adrenaline and pivalic acid, is a prodrug of adrenaline. The addition of pivaloyl groups to the adrenaline molecule enhances the lipophilicity of the molecule increasing its penetration into the anterior chamber of the eye.

Following topical application to the eye, dipivefrine hydrochloride is rapidly and almost completely hydrolysed to adrenaline by esterases present mainly in the cornea, conjunctiva and aqueous humour. The use of the prodrug delivery system enhances the delivery of adrenaline (transcorneal passage of dipivefrine hydrochloride has been reported as being 17 times greater than adrenaline¹), reducing the amount of drug that is required to achieve an equivalent therapeutic effect, therefore, minimising the incidence rates of side effects that are associated with conventional adrenaline therapy.

In humans, dipivefrine and its metabolites have been detected in the cornea and aqueous humour, however, distribution of dipivefrine and its metabolites has not been fully characterised. Dipivefrine also appears to be distributed into tissues and fluids of the contralateral eye. Systemic distribution of dipivefrine following topical application of drug to the eye in humans has not been determined.

Indications

DIPOQUIN Eye Drops 0.1% are indicated for the treatment of open-angle glaucoma alone or in combination with other glaucoma medications. In many cases reduction of intraocular pressure may be obtained when miotics have failed.

Dosage and Administration

One drop of DIPOQUIN Eye Drops 0.1% should be instilled into the affected eye(s) two times per day. Since DIPOQUIN Eye Drops 0.1% may be used with other ocular glaucoma therapies, it is important to advise the patient to allow at least a five minute interval between instillation of each medication to prevent washout of the previous dose.

In order to minimise systemic absorption, apply pressure to the tear duct for two minutes immediately after administration.

Contraindications

Dipivefrine hydrochloride is contraindicated in patients with narrow angles since any dilation of the pupil may predispose the patient to an attack of angle-closure glaucoma. Dipivefrine hydrochloride is also contraindicated in patients with known hypersensitivities to adrenaline, dipivefrine hydrochloride or to any other ingredient of DIPOQUIN Eye Drops 0.1% (see FURTHER INFORMATION).

Warnings and Precautions

Extreme caution is required if this product is prescribed for a patient for whom the aetiology of the glaucoma has not been established.

Dipivefrine hydrochloride should be used with caution in aphakic patients because of the possibility of cystoid macular oedema and other macular toxicity.

Although systemic adverse effects are less likely following ophthalmic use of dipivefrine hydrochloride than adrenaline, the cardiovascular status of the patient should be considered before initiating dipivefrine hydrochloride therapy. Dipivefrine hydrochloride should be used with caution in patients with vascular hypertension or cardiac disorders, including arrhythmias and cardiovascular disease, since ophthalmic use of adrenaline has been associated with adverse cardiovascular effects.

If patients continue to wear soft (hydrophilic) contact lenses while under treatment with DIPOQUIN Eye Drops 0.1%, they should remove their lens(es) prior to instilling the drops in the affected eye(s). Lens(es) should not be inserted into the eye(s) until 15 minutes after instillation of the drops.

A small percentage of patients have reported blurred vision following the topical administration of dipivefrine hydrochloride (see ADVERSE EFFECTS). Patients should be warned to exercise caution in operating machinery and/or driving if any change to vision is evident.

It is not known if topically applied dipivefrine is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised if dipivefrine is administered to a breastfeeding woman.

No studies have been conducted to evaluate the carcinogenic or mutagenic potential of dipivefrine hydrochloride administered topically.

Fertility studies have been conducted in male and female rats at doses up to 0.5 mg/kg/day, administered subcutaneously, to determine the effect of the drug on reproductive ability and early foetal development. Administration of dipivefrine hydrochloride during pre-mating, mating and early gestation was determined to have no adverse effects on the fertility of parent animals or on foetal development.

Adverse Effects

In comparison with topical adrenaline, the topical administration of dipivefrine hydrochloride is generally associated with milder, less frequent, adverse events. The most frequent adverse events associated with topical dipivefrine hydrochloride are ocular.

Prolonged use of topical dipivefrine hydrochloride may be associated with adverse events such as blepharoconjunctivitis, bulbar conjunctival follicles, conjunctival hyperaemia and karyomegaly of the conjunctival cells. Such reactions may necessitate the discontinuance of the drug.

The most frequent adverse events associated with topical dipivefrine hydrochloride are ocular congestion or hyperaemia and burning or stinging (occurring in approximately 6% of patients). Ocular discomfort, resulting from photophobia, glare or light sensitivity has occurred in approximately 2% of patients. Mydriasis, blurred vision (possibly related to mydriasis), ocular pain and headache, associated with local ocular effects, have also been reported. Mild asymptomatic conjunctival hyperaemia has been observed following prolonged (30 months) therapy with dipivefrine hydrochloride.

Ophthalmic use of adrenaline has been reported to occasionally cause systemic sympathomimetic effects, including tachycardia, arrhythmias and hypertension. Such effects occur less frequently following the topical administration of dipivefrine hydrochloride.

Interactions

Interactions between dipivefrine hydrochloride and inhalation anaesthetics, tricyclic antidepressants, digitalis glycosides and systemic sympathomimetics may be observed. The degree of interaction may be dependant upon the amount of each drug that is present.

The IOP lowering effect of dipivefrine hydrochloride may be enhanced when used in conjunction with topical miotics, topical β-adrenergic blocking agents, and/or systemically administered carbonic anhydrase inhibitors.

The effect of concomitant use of dipivefrine hydrochloride and ecothiopate in lowering IOP appears to be at least equal to that of concomitant adrenaline and ecothiopate.

While well controlled, comparative studies may be lacking, the concomitant use of dipivefrine hydrochloride and timolol generally appears to be less effective in lowering IOP than concomitant pilocarpine and timolol, as effective as concomitant adrenaline and timolol and, at least in the short term, more effective than timolol and dipivefrine hydrochloride alone.

The concomitant use of dipivefrine hydrochloride and betaxolol hydrochloride is also lacking well controlled, comparative studies. Available data, however, suggest that the concomitant use of dipivefrine hydrochloride and betaxolol hydrochloride has a greater effect than either betaxolol hydrochloride or dipivefrine hydrochloride alone, and is also superior to any additive action seen with the combination of dipivefrine hydrochloride and timolol².

Overdosage

No information on overdosage is available in humans. A topical overdose of DIPOQUIN Eye Drops 0.1% may be flushed from the eyes with warm tap water. Adrenaline, the pharmacologically active form of dipivefrine hydrochloride, does not reach pharmacologically active concentrations in the body following oral administration because it is rapidly conjugated and oxidised in the gastrointestinal mucosa and liver. Following an accidental overdosage per ora, treatment should be supportive in accord with any symptoms that are observed.

Pharmaceutical Precautions

Medicine Classification

Package Quantities

Further Information

Chemical structure:

Chemical names: (±)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl alcohol 3,4-dipivalate hydrochloride.

Name and Address

Pacific Pharmaceuticals Ltd
PO Box 11-183
Ellerslie
AUCKLAND
Telephone: 09-579-2792

INFORMATION FOR HEALTH PROFESSIONALS