4.1. Therapeutic indications

Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution diminishes over time in most patients. Although some patients have received successful treatment with Apraclonidine 0.5% w/v Eye Drops, Solution for longer periods, the benefit for most patients is less than one month.

The addition of Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution is an aqueous suppressing drug and the addition of a third aqueous suppressant may not significantly reduce IOP.

4.2. Posology and method of administration

Posology

One drop of Apraclonidine 0.5% w/v Eye Drops, Solution should be instilled into the affected eye(s) three times per day (t.i.d.). Since Apraclonidine 0.5% w/v Eye Drops, Solution 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. Eye ointments should be administered last. If, for any reason, the drop of Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution for longer periods.

There are no special precautions for administration to the elderly.

Paediatric Population

The safety and efficacy of Apraclonidine 0.5% w/v Eye Drops, Solution in children has not been established. No data are available.

Method of administration

For ocular use only.

After cap is removed, if tamper evident snap collar is loose, remove before using product.

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.

4.3. Contraindications

Apraclonidine 0.5% w/v Eye Drops, Solution is contraindicated in patients with a history of severe or unstable and uncontrolled cardiovascular disease including severe uncontrolled arterial hypertension. Apraclonidine 0.5% w/v Eye Drops, Solution is contraindicated in children Apraclonidine 0.5% w/v Eye Drops, Solution 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.

4.4. Special warnings and precautions for use

While the topical administration of Apraclonidine 0.5% w/v Eye Drops, Solution 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.

Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution therapy, treatment should be suspended.

As with all glaucoma patients on maximally tolerated medical therapy, those who are treated with Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution 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, and oedema of the lids and conjunctival oedema (see section 4.8). If such ocular symptoms occur, Apraclonidine 0.5% w/v Eye Drops, Solution 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.

Apraclonidine 0.5% w/v Eye Drops, Solution contains benzalkonium chloride

This medicine contains 0.5 mg, 1mg benzalkonium chloride in 5mL, 10mL of the product respectively, which is equivalent to a concentration of 0.1 mg/ml.

Apraclonidine 0.5% w/v Eye Drops, Solution contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients must be instructed to remove contact lenses prior to the application of Apraclonidine 0.5% w/v Eye Drops, Solution and wait 15 minutes after instillation of the dose before reinsertion.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use.

4.5. Interaction with other medicinal products and other forms of interaction

Apraclonidine 0.5% w/v Eye Drops, Solution is contraindicated in patients receiving monoamine oxidase inhibitors, systemic sympathomimetics or tricyclic antidepressants (see section 4.3).

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 Apraclonidine 0.5% w/v Eye Drops, Solution, 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 Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution should have pulse and blood pressure frequently monitored. Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart. Eye ointments should be administered last.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited studies of Apraclonidine 0.5% w/v Eye Drops, Solution in pregnant women. Apraclonidine 0.5% w/v Eye Drops, Solution is not recommended during pregnancy

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 Apraclonidine 0.5% w/v Eye Drops, Solution based on a 50kg person.

Breastfeeding

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

A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Apraclonidine 0.5% w/v Eye Drops, Solution.

Fertility

Studies have not been performed to evaluate the effect of topical ocular administration Apraclonidine 0.5% w/v Eye Drops, Solution on male or female fertility. No effect on fertility was observed in rats after oral administration of apraclonidine.

4.7. Effects on ability to drive and use machines

Apraclonidine 0.5% w/v Eye Drops, Solution has a moderate influence on the ability to drive and use machines.

Since clonidine-like drugs may cause dizziness or 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.

4.8. Undesirable effects

Summary of the safety profile

In clinical trials using Apraclonidine 0.5% w/v Eye Drops, Solution the most common adverse reactions were ocular hyperaemia, eye pruritus, and conjunctivitis, occurring in approximately 12% to 23% of patients.

The following adverse reactions are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Classification

MedDRA Preferred Term (v. 19.0)

Infections and infestations

Common: rhinitis

Immune system disorders

Not known: hypersensitivity

Psychiatric disorders

Uncommon: depression, nervousness, insomnia

Nervous system disorders

Common: headache, dysgeusia

Uncommon: dizziness, abnormal coordination, somnolence, paraesthesia

Eye disorders

Very common: conjunctivitis, eye pruritus, ocular hyperaemia

Common: eyelid oedema, dry eye, conjunctival follicles, foreign body sensation in eyes, eyelid margin crusting, lacrimation increased, ocular discomfort

Uncommon: mydriasis, keratitis, keratopathy, visual acuity reduced, visual impairment, photophobia, vision blurred, corneal erosion, corneal infiltrates, blepharospasm, blepharitis, eyelid ptosis, erythema of eyelid, eye pain, eye oedema, eyelid disorder, eyelid scales, eye lid retraction, conjunctival vascular disorders, conjunctival oedema, eye discharge, eye irritation

Cardiac disorders

Uncommon: chest pain, oedema peripheral, arrhythmia

Vascular disorders

Uncommon: vasodilation

Respiratory, thoracic and mediastinal disorders

Common: nasal dryness

Uncommon: asthma, dyspnoea, rhinorrhoea, parosmia, throat irritation

Gastrointestinal disorders

Common: dry mouth

Uncommon: nausea, constipation

Skin and subcutaneous tissue disorders

Common: dermatitis

Uncommon: dermatitis contact, face oedema

Muscoskeletal and connective tissue disorders

Uncommon: myalgia

General disorders and administration site conditions

Common: asthenia

Uncommon: malaise, fatigue, irritability

Investigations

Uncommon: corneal staining

Description of selected adverse reactions

Use of Apraclonidine 0.5% w/v Eye Drops, Solution 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 Apraclonidine 0.5% w/v Eye Drops, Solution 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 possibility of bradycardia based on apraclonidine's alpha-2-adrenergic agosnist effect should be considered. Although there were no reports of bradycardia related to Apraclonidine 0.5% w/v Eye Drops, Solution Eye Drops from clinical studies, occasional reports have been received through postmarketing surveillance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Apraclonidine 0.5% w/v Eye Drops, Solution may be flushed from the eyes with lukewarm water or sterile saline solution.

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.