IOPIDINE 5 mg/ml, Eye Drops, Solution

Apraclonidine 5 mg/ml (as hydrochloride)

For excipients, see section 6.1.

Eye drops, solution.

A colourless to pale yellow solution.

IOPIDINE 5 mg/ml is indicated for short-term adjunctive therapy of chronic glaucoma in patients on maximally tolerated medical therapy who require additional intraocular pressure (IOP) reduction to delay laser treatment or glaucoma surgery.

The IOP lowering efficacy of IOPIDINE 5mg/ml diminishes over time in most patients. Although some patients have received successful treatment with IOPIDINE 5mg/ml for longer periods, the benefit for most patients is less than one month.

The addition of IOPIDINE 5mg/ml to patients already using two aqueous suppressing drugs (i.e. beta-blockers plus carbonic anhydrase inhibitor) as part of their maximally tolerated medical therapy may not provide additional benefit. This is because IOPIDINE 5mg/ml is an aqueous suppressing drug and the addition of a third aqueous suppressant may not significantly reduce IOP.

Adults (including the elderly)

One drop of IOPIDINE 5 mg/ml should be instilled into the affected eye(s) three times per day (t.i.d.). Since IOPIDINE 5mg/ml will be used with other ocular glaucoma therapies, an approximate five minute interval between instillation of each medication should be observed to prevent washout of the previous dose. If, for any reason, the drop of IOPIDINE 5mg/ml does not remain in the eye, then the patient should repeat the dose by placing another drop in the eye. The maximum recommended duration of therapy is one month due to loss of effect over time (tachyphylaxis). However, some patients may benefit from treatment with IOPIDINE 5 mg/ml for longer periods.

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medications administered via the ocular route and result in a decrease in systemic side effects.

There are no special precautions for administration to the elderly.

Children

Clinical studies to establish safety and efficacy in children have not been conducted and, therefore, IOPIDINE 5 mg/ml is not recommended for use in children under 12 years of age.

IOPIDINE 5 mg/ml is contraindicated in children, in patients with a history of severe or unstable and uncontrolled cardiovascular disease, including severe uncontrolled arterial hypertension.

IOPIDINE 5 mg/ml is contraindicated in patients with hypersensitivity to any component of the formulation or to systemic clonidine and in patients receiving monoamine oxidase inhibitors, systemic sympathomimetics or tricyclic antidepressants.

Warnings:

For topical ophthalmic use only. Not for injection or oral ingestion.

While the topical administration of IOPIDINE 5mg/ml had minimal effect on heart rate or blood pressure in clinical studies evaluating glaucoma patients including those with cardiovascular disease, the possibility of a vasovagal attack should be considered and caution should be exercised in patients with a history of such episodes. IOPIDINE 5mg/ml should be used with caution in patients with a history of angina, severe coronary insufficiency, recent myocardial infarction, overt cardiac failure, hypertension, cardiovascular disease including apoplexy, cerebrovascular disease, Parkinson's syndrome, chronic renal failure, Raynaud's disease or thromboangiitis obliterans. Caution in and monitoring of depressed patients are advised since apraclonidine has been rarely associated with depression.

In end-stage glaucoma, if reduction in vision occurs immediately following IOPIDINE 5 mg/ml therapy, treatment should be suspended.

Precautions:

As with all glaucoma patients on maximally tolerated medical therapy, those who are treated with IOPIDINE 5 mg/ml to delay surgery should have frequent follow-up examinations and treatment should be discontinued if the intraocular pressure rises significantly. The loss of effect which occurs over time in most patients appears to be an individual occurrence with a variable time of onset and should be closely monitored. Furthermore, these patients should have their visual fields evaluated periodically.

No data are available on the topical use of apraclonidine in patients with renal or hepatic failure. Systemic absorption of apraclonidine following topical administration is low, resulting in plasma levels less than 1.0 ng/ml. Nonetheless, monitoring of patients with impaired renal or hepatic function is advised. Close monitoring of cardiovascular parameters in patients with impaired liver function is also advised as the systemic dosage form of clonidine is partly metabolised in the liver.

Use of IOPIDINE 5mg/ml can result in an ocular intolerance reaction characterised wholly or in part by the symptoms of ocular hyperaemia, eye pruritus, ocular discomfort, lacrimation increased, abnormal sensation in eye, eyelid oedema and conjunctival oedema (see section 4.8). If such ocular symptoms occur, IOPIDINE 5mg/ml therapy should be discontinued. Also, preclinical data suggest that there may be patients who develop a contact sensitization response with repeated use of the drug. Ocular intolerance responses are more common in patients treated for more than one month.

Discontinuation of therapy in the event of rising intraocular pressure should coincide with the initiation of alternative therapy, or pressure-relieving surgery.

Since apraclonidine is a potent depressor of intraocular pressure, patients who develop an exaggerated reduction in intraocular pressure should be closely monitored.

As IOPIDINE 5mg/ml contains the preservative benzalkonium chloride, this may cause irritation and is known to discolour soft contact lenses. Therefore, patients must remove contact lenses prior to application of IOPIDINE and be instructed to wait 15 minutes after instillation of IOPIDINE before inserting contact lenses.

The risk of clinically relevant interactions appears low, considering the plasma levels of apraclonidine given by the ocular route. No drug interactions were reported in those patients who were receiving concomitant medication for glaucoma or for other ocular disorders or for any systemic disease present during clinical studies. Although no specific drug interactions with topical glaucoma drugs or systemic medicaments were identified in clinical studies of IOPIDINE 5mg/ml, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, anaesthetics) should be considered. There is a theoretical possibility that use of IOPIDINE 5 mg/ml in conjunction with topical sympathomimetics may give rise to a systemic pressor response and blood pressure should be checked initially in patients receiving these drug combinations.

Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

An additive hypotensive effect has been reported with the combination of systemic clonidine and neuroleptic therapy. Systemic clonidine may inhibit the production of catecholamine in response to insulin-induced hypoglycaemia and mask the signs and symptoms of hypoglycaemia.

Since apraclonidine may reduce pulse and blood pressure, caution in using drugs such as beta-blockers (ophthalmic and systemic), antihypertensives, and cardiac glycosides is advised. Patients using cardiovascular drugs concurrently with IOPIDINE 5 mg/ml should have pulse and blood pressure frequently monitored. Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents.

There are no studies of IOPIDINE 5 mg/ml in pregnant women. IOPIDINE 5 mg/ml should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.

Animal studies have been conducted which have demonstrated an absence of teratogenic effects in rats and rabbits. Embryotoxicity has been observed when pregnant rabbits were dosed orally with doses of apraclonidine (doses>1.25 mg/kg/day) that were maternally toxic, and administered over the entire period of organogenesis at exposure levels of (mg/kg/day) of>60 times the recommended dosage regimen for IOPIDINE 5mg/ml Eye Drops based on a 50 kg person.

It is not known if topically applied apraclonidine is excreted in human milk.

Since many drugs are excreted in human milk, caution should be exercised when IOPIDINE 5 mg/ml is administered to nursing women.

Since clonidine-like drugs may cause somnolence, patients so affected are advised not to drive or operate machinery. The attention of drivers and machinery operators should be drawn to the risks related to the use of this drug.

Use of IOPIDINE 5 mg/ml can lead to an ocular intolerance reaction (see section 4.4). The mean onset time of these reactions was 44 days (range 1-127 days).

In clinical studies, the overall discontinuation rate related to IOPIDINE 5 mg/ml was 15%. The most commonly reported events leading to discontinuation included (in decreasing order of frequency) ocular hyperaemia, eye pruritus, lacrimation increased, ocular discomfort, eyelid oedema, dry mouth, and abnormal sensation in eye.

The following adverse reactions (incidences) were reported in clinical studies of IOPIDINE 5 mg/ml as being possibly, probably, or definitely related to therapy:

Infections and Infestations

Uncommon (0.1% <1%): pharyngitis, rhinitis.

Psychiatric Disorders

Uncommon (0.1% <1%): nervousness, depression, insomnia.

Nervous System Disorders

Common (1% <10%): headache, dysgeusia.

Uncommon (0.1% <1%): abnormal coordination, somnolence, dizziness, paraesthesia.

Eye Disorders

Very Common (10%): ocular hyperaemia, eye pruritus.

Common (1% <10%): ocular discomfort, lacrimation increased, eyelid oedema, vision blurred, abnormal sensation in eye, keratoconjunctivitis sicca, conjunctivitis, eye discharge, conjunctival vascular disorder (blanching).

Uncommon (0.1% <1%): eyelid margin crusting, conjunctival follicles, conjunctival oedema eye oedema, visual disturbance, eye pain, eyelid disorder, keratitis, blepharitis, photophobia, erythema of eyelid, eye irritation, corneal erosion, corneal infiltrates, keratopathy, eyelid scales, eyelid retraction.

Cardiac Disorders

Uncommon (0.1% <1%): chest pain, oedema peripheral, arrhythmia.

The possibility of bradycardia based on apraclonidine's alpha-2-adrenergic agonist effect should be considered. Although there were no reports of bradycardia related to IOPIDINE 5 mg/ml Eye Drops from clinical studies, occasional reports have been received through postmarketing surveillance.

Respiratory, Thoracic and Mediastinal Disorders

Common (1% <10%): nasal dryness.

Uncommon (0.1% <1%): dyspnoea, asthma, parosmia.

Gastrointestinal Disorders

Very Common (10%): dry mouth.

Uncommon (0.1% <1%): constipation, nausea.

Skin and Subcutaneous Tissue Disorders

Uncommon (0.1% <1%): dermatitis contact, dermatitis, face oedema.

Musculoskeletal and Connective Tissue Disorders

Uncommon (0.1% <1%): myalgia.

General Disorders and Administration Site Conditions

Common (1% <10%): asthenia.

Uncommon (0.1% <1%): malaise.

Investigations

Uncommon (0.1% <1%): corneal staining.

IOPIDINE 5 mg/ml may be flushed from the eyes with water or sterile saline solution.

A 23 month old male child ingested orally an unknown amount of IOPIDINE 5mg/ml. The child was admitted to the hospital with hypothermia, bradycardia, and drowsiness. Blood analysis revealed an apraclonidine serum level of 2.9ng/ml. The child was warmed and treated with atropine and dopamine with resolution of hypothermia and bradycardia within 4 hours. The child remained somnolent for 24 hours and was discharged 48 hours after admission with no reported sequelae. Accidental or intentional ingestion of oral clonidine has been reported to cause hypotension, transient hypertension, asthenia, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, sedation or coma, pallor, hypothermia, bradycardia, conduction defects, arrhythmias, dryness of the mouth, miosis, apnoea, respiratory depression, hypoventilation, and seizure. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. Haemodialysis is of limited value, since a maximum of 5% of circulating drug is removed.

Apraclonidine is a relatively selective alpha-2-adrenergic agonist which does not possess significant membrane stabilising (local anaesthetic) activity. When instilled into the eye, apraclonidine has the action of reducing intraocular pressure. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters. Aqueous fluorophotometry studies in man suggest that the mechanism of the ocular hypotensive action of apraclonidine is related to a reduction in aqueous formation. The onset of action of IOPIDINE 5 mg/ml Eye Drops can usually be noted within one hour and the maximum intraocular pressure reduction usually occurs three to five hours after application of a single dose.

The ATC code is SO1E A03.

Following topical ocular administration to New Zealand White rabbits, apraclonidine reached peak concentrations after two hours in the aqueous humour, iris, ciliary body and lens. The cornea exhibited the greatest concentration and peaked at the earliest time point (20 minutes). The tissue distribution of apraclonidine from highest to lowest concentration in microgram equivalents per gram of tissue was cornea, iris-ciliary body, aqueous humour, lens and vitreous humour. The elimination half-life of apraclonidine from the aqueous humour was determined to be approximately two hours.

Plasma concentration of apraclonidine following three times daily, bilateral, topical ocular dosing of IOPIDINE 5 mg/ml to normal human volunteers was less than 1.0 ng/ ml. A steady state level was attained after five days of dosing. The half-life of the drug was calculated to be eight hours.

Administration of apraclonidine intravenously and via the topical ocular route to both cats and monkeys resulted in a reduced anterior segment blood flow, whereas flow to the posterior segment, i.e., retina, choroid or optic nerve head, was not affected. Chronic treatment of primates with apraclonidine hydrochloride 15 mg/ml ocularly three times a day for one year did not result in morphologic effects which would be indicative of vasoconstriction of the anterior or posterior segments of the eye. Although ocular blood flow studies have not been conducted in humans, the animal studies provide a basis for the safe use of this drug in the treatment of chronic glaucoma.

Acute Toxicity

The oral LD ₅₀ ranged from 5mg/kg (mice) to 64 mg/kg (rats); no lethalities were observed in primates at 55 mg/kg.

Subchronic and Chronic Toxicity

Oral administration

Rats and mice received daily oral doses of up to 1.2 mg/kg and 2 mg/kg, respectively, over a period of 13 weeks. Mortalities occurred from 1.2 mg/kg/day to 1.6 mg/kg/day. Disturbed defaecation, distended abdomen and corneal cloudiness have been observed.

Local administration

The topical ocular administration of apraclonidine hydrochloride solutions (2 drops instilled at 30 minute intervals into one eye for 6 hours) led to dose-dependent conjunctival and corneal irritation in the rabbit from 5 mg/ml.

Rabbits tolerated a solution of 15 mg/ml (2 drops t.i.d.) over a period of one month without signs of systemic toxicity. Nevertheless, conjunctival irritation and sporadic minimal corneal cloudiness have been observed.

No drug-related ophthalmic or systemic findings were observed when monkeys received apraclonidine hydrochloride solutions of 5, 10 and 15 mg/ml by topical ocular administration t.i.d. for one year

Local tolerance

Assessment of the sensitisation potential in the guinea pig proved apraclonidine hydrochloride to be moderately sensitising.

Mutagenic and Tumorigenic Potential

Mutagenicity testing of apraclonidine hydrochloride using different standard systems all produced negative results. Nevertheless, ocular (keratitis) and renal effects have been reported during these tumorigenic studies.

Reproduction toxicity

Although studies performed in rats and rabbits did not suggest any teratogenic action, slight foetal toxicity was observed at 60 times the therapeutic dosage.

Benzalkonium chloride, Sodium acetate (trihydrate), Sodium chloride, Hydrochloric acid and/or Sodium hydroxide and Purified water.

Not applicable.

3 years. After first opening one month.

Do not store above 25°C. Do not refrigerate or freeze.

Keep the container in the outer carton.

5 ml or 10 ml white LDPE DROP-TAINER dispensers with a natural LDPE dispensing plug and white polypropylene closure.

Not all pack sizes may be marketed.

No special requirements.

Alcon Laboratories (UK) Ltd.,

Pentagon Park,

Boundary Way,

Hemel Hempstead,

Hertfordshire, HP2 7UD,

United Kingdom.

PL 0649/0132

29 December 1994/Renewed 2 December 2004

November 2004