4.1. Therapeutic indications

Apraclonidine 1% w/v Eye Drops, Solution is indicated to control or prevent post surgical elevations in intraocular pressure that occur in patients after anterior segment laser surgery. (Clinical trials have been conducted in trabeculoplasty, iridotomy and capsulotomy).

4.2. Posology and method of administration

For topical ophthalmic use only.

Adults (including the elderly):

One drop of Apraclonidine 1% w/v Eye Drops, Solution should be instilled into the eye scheduled for operation one hour before initiating anterior segment laser surgery. A second drop should be instilled into the same eye immediately upon completion of the laser surgical procedure.

If for any reason, the drop of Apraclonidine 1% w/v Eye Drops, Solution does not remain in the eye, repeat the dose by placing another drop in the eye.

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.

Paediatric population

Safety and effectiveness of Apraclonidine 1% w/v Eye Drops, Solution in children have not been established and therefore Apraclonidine 1% w/v Eye Drops, Solution is not recommended for use in children.

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

4.3. Contraindications

In patients with a history of severe or unstable and uncontrolled cardiovascular disease.

For use in children,

In patients receiving monoamine oxidase inhibitor therapy, systemic sympathomimetic agents, tricyclic antidepressants,

In patients with hypersensitivity to the active substances (clonidine or apraclonidine) or to any of the excipients

4.4. Special warnings and precautions for use

Warnings:

While the topical administration of two drops of Apraclonidine 1% w/v Eye Drops, Solution had minimal effect on heart rate or blood pressure in clinical studies evaluating patients undergoing anterior segment laser surgery, 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 1% 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, cerebrovascular disease, 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.

Precautions:

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.

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

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

The risk of clinically relevant interactions appears low considering the plasma levels of apraclonidine given by the ocular route.

Apraclonidine 1% w/v Eye Drops, Solution is contraindicated in patients receiving monoamine oxidase inhibitors (see section 4.3).

Although no specific drug interactions with topical glaucoma drugs or systemic medicaments were identified in clinical studies of Apraclonidine 1% 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 1% 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 1% 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Apraclonidine 1% w/v Eye Drops, Solution in pregnant women. Preclinical studies with apraclonidine have shown embryotoxicity (see section 5.3).

The potential risk for humans is unknown. Apraclonidine 1% w/v Eye Drops, Solution is therefore not recommended for use during pregnancy

Breast-feeding

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

A risk to the new borns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Apraclonidine 1% w/v Eye Drops, Solution

Fertility

Studies have not been performed to evaluate the effect of topical ocular administration of Apraclonidine 1% 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 1% w/v Eye Drops, Solution may cause dizziness and drowsiness; patients if so affected should not drive or operate machinery.

4.8. Undesirable effects

Summary of safety profile

In clinical trials, the most common adverse drug reaction was dry mouth which occurred in 5.6% of patients. Other common adverse drug reactions included eyelid retraction and mydriasis, occurring in approximately 3% to 4% of patients. All other drug reactions occurred in less than 2% of patients.

The following adverse reactions have been reported from clinical studies and post marketing surveillance and are classified according to the subsequent 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) and very rare (<1/10,000) or not known (frequency cannot be estimated from available data. Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Classification

MedDRA Preferred Term (v.19.0)

Immune systems disorders

Not known: Hypersensitivity

Nervous System Disorders

Common: Dysgeusia.

Uncommon: Syncope vasovagal, paraesthesia, libido decreased, irritability, dizziness postural, headache.

Rare:: Hypoaesthesia,.

Eye Disorders

Common : Ocular hyperaemia, mydriasis, dry eye, abnormal sensation in eye, eyelid retraction, eye disorder (conjunctival blanching)

Uncommon : Conjunctival haemorrhage, eye inflammation, eyelid disorder (upper lid elevation), hypotony of eye, visual acuity reduced (dim vision),, vision blurred, eye allergy, eyelid disorder (upper lid elevation), eye pruritus, dry eye, eye irritation, ocular discomfort, punctate keratitis

Cardiac Disorders

Uncommon : Heart rate irregular, Bradycardia, palpitations.

Psychiatric Disorders

Uncommon : Insomnia, abnormal dreams.

Respiratory, Thoracic and Mediastinal Disorders

Common: Nasal dryness

Rare: Dyspnoea, increased upper airway secretion, nasal discomfort,

Vascular Disorders

Uncommon Orthostatic hypotension.

Not known: hypotension,

hypertension

Gastrointestinal Disorders

Common: Dry mouth

Uncommon: Diarrhoea, vomiting, abdominal pain, stomach discomfort, nausea

Skin and Subcutaneous Tissue Disorders

Rare: Hyperhidrosis, pruritus.

Musculoskeletal, Connective Tissue and Bone Disorders

Rare : Pain in extremity.

General Disorders and Administration Site Conditions

Common: Fatigue

Rare: Chest pain, , feeling hot, feeling hot and cold.

Paediatric population

Apraclonidine 1% w/v Eye Drops, Solution is contraindicated for use in children. Reactions including lethargy, bradycardia and decreased oxygen saturation have been reported in neonates and infants under 1 year of age even when a single dose of apraclonidine was administered (See sections 4.3 and 4.9).

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

In the case of accidental overdose, Apraclonidine 1% w/v Eye Drops, Solution can be removed by rinsing the eye with water or sterile saline solution.

A 2 month old female child received Apraclonidine 1% w/v Eye Drops, Solution 1 drop in each eye. Two to three hours later, the infant presented with extreme pallor, hypothermia and miosis. She became comatose and was treated with glucose perfusion. The infant became responsive, but lethargic and heart rate was noted to be slow but regular. The infant made a full recovery with no sequelae.

A 23 month old male child ingested orally an unknown amount of IOPIDINE 5 mg/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.

Overdose with the oral form of 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.