SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

IOPIDINE 5mg/ml Eye Drops, Solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains Apraclonidine 5 mg (as hydrochloride).

Excipients:

1 ml of solution contains 0.1 mg benzalkonium chloride For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Eye drops, solution.

A colourless to pale yellow solution

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

IOPIDINE 5mg/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 diminishes over time in most patients.

Although some patients have received successful treatment with IOPIDINE for longer periods, the benefit for most patients is less than one month.

The addition of IOPIDINE 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 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 IOPIDINE should be instilled into the affected eye(s) three times per day (t.i.d.). Since IOPIDINE 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 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 for longer periods.

There are no special precautions for administration to the elderly.

Paediatric Population

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

Method of administration

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

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

IOPIDINE 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

Warnings:

For ocular use only. Not for injection or oral ingestion.

While the topical administration of IOPIDINE 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 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 therapy, treatment should be suspended.

Precautions:

As with all glaucoma patients on maximally tolerated medical therapy, those who are treated with IOPIDINE 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 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, IOPIDINE 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 contains the preservative benzalkonium chloride, this may cause eye irritation and is known to discolour soft contact lenses. Avoid contact with 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.

4.5 Interaction with other medicinal products and other forms of interaction

IOPIDINE 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 IOPIDINE, 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 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 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.

4.6    Fertility, Pregnancy and lactation

Fertility

Studies have not been performed to evaluate the effect of topical ocular administration of IOPIDINE on fertility.

Pregnancy

There are no or limited studies of IOPIDINE in pregnant women.

IOPIDINE 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 IOPIDINE Eye Drops based on a 50kg person.

Lactation

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

A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with IOPIDINE.

4.7    Effects on ability to drive and use machines

IOPIDINE 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 IOPIDINE 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. 12.1)
Infections and infestations	Common: rhinitis
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, eye lid 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	Common: nasal dryness
disorders	Uncommon: asthma, dyspnoea, rhinorrhoea, parosmia, throat irritation
Gastrointestinal disorders	Common: dry mouth Uncommon: nausea, constipation
Skin and subcutaneous tissue	Common; dermatitis
disorders	Uncommon: dermatitis contact, face oedema,
Muscoskeletal and connective tissue disorders	Uncommon: myalgia
General disorders and administration	Common: asthenia
site conditions	Uncommon: malaise, fatigue, irritability
Investigations	Uncommon: corneal staining

Description of selected adverse reactions

Use of IOPIDINE 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 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 IOPIDINE Eye Drops from clinical studies, occasional reports have been received through postmarketing surveillance.

4.9    Overdose

IOPIDINE 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.

5.    PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Ophthalmologicals; Antiglaucoma Preparation and Miotics.

ATC code: SO1E A03.

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.

5.2 Pharmacokinetic properties

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 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.

5.3. Preclinical safety data

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 15mg/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 LD₅₀ 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 5mg/ml.

Rabbits tolerated a solution of 15mg/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 15mg/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.

6. PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Benzalkonium chloride Sodium acetate (trihydrate)

Sodium chloride

Hydrochloric acid and/or Sodium hydroxide (for pH adjustment)

Purified water.

6.2.    Incompatibilities

Not applicable

6.3.    Shelf life

3    years.

4    weeks after first opening

6.4.    Special precautions for storage

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

Keep the container in the outer carton.

6.5.    Nature and contents of container

5    ml and/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.

6.6.    Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Alcon Laboratories (UK) Limited Frimley Business Park,

Frimley, Camberley,

Surrey, GU16 7SR, United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 00649/0132

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 December 1994/ Renewed 20 October 2010

10    DATE OF REVISION OF THE TEXT

28/04/2014