IOPIDINE® 0.5% Ophthalmic Solution contains apraclonidine hydrochloride, an alpha adrenergic agonist, in a sterile isotonic solution for topical application to the eye. Apraclonidine hydrochloride is a white to off-white powder and is highly soluble in water. Its chemical name is 2-[(4-amino-2,6 dichlorophenyl) imino]imidazolidine monohydrochloride with an empirical formula of C₉H₁₁C_l3N₄ and a molecular weight of 281.57. The chemical structure of apraclonidine hydrochloride is:

Each mL of IOPIDINE 0.5% Ophthalmic Solution contains

Active: apraclonidine hydrochloride 5.75 mg equivalent to apraclonidine base 5 mg; Preservative: benzalkonium chloride 0.01%. Inactives: sodium chloride, sodium acetate, sodium hydroxide and/or hydrochloric acid (pH 4.4-7.8) and purified water.

Last updated on RxList: 1/24/2005

IOPIDINE 0.5% Ophthalmic Solution is indicated for short-term adjunctive therapy in patients on maximally tolerated medical therapy who require additional IOP reduction. Patients on maximally tolerated medical therapy who are treated with IOPIDINE 0.5% Ophthalmic Solution to delay surgery should have frequent followup examinations and treatment should be discontinued if the intraocular pressure rises significantly.

The addition of IOPIDINE 0.5% Ophthalmic Solution to patients already using two aqueous suppressing drugs (i.e., beta-blocker plus carbonic anhydrase inhibitor) as part of their maximally tolerated medical therapy may not provide additional benefit. This is because IOPIDINE 0.5% Ophthalmic Solution is an aqueous suppressing drug and the addition of a third aqueous suppressant may not significantly reduce IOP.

The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in some patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a variable time of onset and should be closely monitored. The benefit for most patients is less than one month.

One to two drops of IOPIDINE 0.5% Ophthalmic Solution should be instilled in the affected eye(s) three times daily. Since IOPIDINE 0.5% Ophthalmic Solution will be used with other ocular glaucoma therapies, an approximate 5 minute interval between instillation of each medication should be practiced to prevent washout of the previous dose. NOT FOR INJECTION INTO THE EYE. NOT FOR ORAL INGESTION.

IOPIDINE 0.5% Ophthalmic Solution as base in a sterile, isotonic, aqueous solution containing apraclonidine hydrochloride.

Supplied in plastic ophthalmic DROP-TAINER® dispenser as follows:

5 mL	NDC 0065-0665-05
10 mL	NDC 0065-0665-10

Storage: Store between 2 - 27°C (36 - 80°F). Protect from freezing and light.

ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA, December 2003 Printed in USA, ©2003 Alcon, Inc.

Last updated on RxList: 1/24/2005

In clinical studies the overall discontinuation rate related to IOPIDINE 0.5% Ophthalmic Solution was 15%. The most commonly reported events leading to discontinuation included (in decreasing order of frequency) hyperemia, pruritus, tearing, discomfort, lid edema, dry mouth, and foreign body sensation.

The following adverse reactions (incidences) were reported in clinical studies of IOPIDINE 0.5% (apraclonidine ophthalmic solution) as being possibly, probably, or definitely related to therapy:

Ocular

The following adverse reactions were reported in 5 to 15% of the patients: discomfort, hyperemia, and puritus. The following adverse reactions were reported in 1 to 5% of the patients: blanching, blurred vision, conjunctivitis, discharge, dry eye, foreign body sensation, lid edema, and tearing.

The following adverse reactions were reported in less than 1% of the patients: abnormal vision, blepharitis, blepharoconjunctivitis, conjunctival edema, conjunctival follicles, corneal erosion, corneal infiltrate, corneal staining, edema, irritation, keratitis, keratopathy, lid disorder, lid erythema, lid margin crusting, lid retraction, lid scales, pain, photophobia.

Nonocular

Dry mouth occurred in approximately 10% of the patients.

The following adverse reactions were reported in less than 3% of the patients: abnormal coordination, asthenia, arrhythmia, asthma, chest pain, constipation, contact dermatitis, depression, dermatitis, dizziness, dry nose, dyspnea, facial edema, headache, insomnia, malaise, myalgia, nausea, nervousness, paresthesia, parosmia, peripheral edema, pharyngitis, rhinitis, somnolence, and taste perversion.

Clinical practice

The following events have been identified during post-marketing use of IOPIDINE® 0.5% Ophthalmic Solution in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to IOPIDINE 0.5% Ophthalmic Solution, or a combination of these factors, include: bradycardia.

Apraclonidine should not be used in patients receiving MAO inhibitors. (See CONTRAINDICATIONS). Although no specific drug interactions with topical glaucoma drugs or systemic medications were identified in clinical studies of IOPIDINE® 0.5% Ophthalmic Solution, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, anesthetics) should be considered. Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with apraclonidine can lead to a reduction in IOP lowering effect. No data on the level of circulating catecholamines after apraclonidine withdrawal are available. Caution, however, 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 catecholamines in response to insulin-induced hypoglycemia and mask the signs and symptoms of hypoglycemia.

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 0.5% Ophthalmic Solution should have pulse and blood pressures frequently monitored. Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents.

Last updated on RxList: 1/24/2005

Not for injection or oral ingestion.

FOR TOPICAL OPHTHALMIC USE ONLY.

General

Glaucoma patients on maximally tolerated medical therapy who are treated with IOPIDINE 0.5% Ophthalmic Solution to delay surgery should have their visual fields monitored periodically.

Although the topical use of IOPIDINE 0.5% Ophthalmic Solution has not been studied in renal failure patients, structurally related clonidine undergoes a significant increase in half-life in patients with severe renal impairment. Close monitoring of cardiovascular parameters in patients with impaired renal function is advised if they are candidates for topical apraclonidine therapy. Close monitoring of cardiovascular parameters in patients with impaired liver function is also advised as the systemic dosage form of clonidine is partly metabolized in the liver.

While the topical administration of IOPIDINE 0.5% Ophthalmic Solution had minimal effect on heart rate or blood pressure in clinical studies evaluating glaucoma patients, the preclinical pharmacology profile of this drug suggests that caution should be observed in treating patients with severe, uncontrolled cardiovascular disease, including hypertension.

IOPIDINE 0.5% Ophthalmic Solution should be used with caution in patients with coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, Raynaud's disease, or thromboangiitis obliterans. Caution and monitoring of depressed patients are advised since apraclonidine has been infrequently associated with depression.

Apraclonidine can cause dizziness and somnolence. Patients who engage in hazardous activities requiring mental alertness should be warned of the potential for a decrease in mental alertness while using apraclonidine.

Topical ocular administration of two drops of 0.5, 1.0 and 1.5% apraclonidine ophthalmic solution to New Zealand albino rabbits three times daily for one month resulted in sporadic and transient instances of minimal corneal edema in the 1.5% group only; no histopathological changes were noted in those eyes.

Use of IOPIDINE 0.5% Ophthalmic Solution can lead to an allergic-like reaction characterized wholly or in part by the symptoms of hyperemia, pruritus, discomfort, tearing, foreign body sensation, and edema of the lids and conjunctiva. If ocular allergic-like symptoms occur, IOPIDINE 0.5% (apraclonidine ophthalmic solution) therapy should be discontinued.

Information for Patients

Do not touch dropper tip to any surface as this may contaminate the contents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No significant change in tumor incidence or type was observed following two years of oral administration of apraclonidine HCl to rats and mice at dosages of 1.0 and 0.6 mg/kg, up to 20 and 12 times, respectively, the maximum dose recommended for human topical ocular use.

Apraclonidine HCl was not mutagenic in a series of in vitro mutagenicity tests, including the Ames test, a mouse lymphoma forward mutation assay, a chromosome aberration assay in cultured Chinese hamster ovary (CHO) cells, a sister chromatid exchange assay in CHO cells, and a cell transformation assay.

An in vivo mouse micronucleus assay conducted with apraclonidine HCl also provided no evidence of mutagenicity.

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at a dose of 0.5 mg/kg (5 to 10 times the maximum recommended human dose).

Pregnancy

Pregnancy Category C: Apraclonidine HCl has been shown to have an embryocidal effect in rabbits when given in an oral dose of 3.0 mg/kg (60 times the maximum recommended human dose). Dose related maternal toxicity was observed in pregnant rats at 0.3 mg/kg (6 times the maximum recommended human dose). There are no adequate and well controlled studies in pregnant women. IOPIDINE 0.5% Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IOPIDINE 0.5% Ophthalmic Solution is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Last updated on RxList: 1/24/2005

Ingestion of IOPIDINE 0.5% Ophthalmic Solution has been reported to cause bradycardia, drowsiness, and hypothermia.

Accidental or intentional ingestion of oral clonidine has been reported to cause apnea, arrhythmias, asthenia, bradycardia, conduction defects, diminished or absent reflexes, dryness of the mouth, hypotension, hypothermia, hypoventilation, irritability, lethargy, miosis, pallor, respiratory depression, sedation or coma, seizure, somnolence, transient hypertension, and vomiting.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. Hemodialysis is of limited value since a maximum of 5% of circulating drug is removed.

IOPIDINE 0.5% Ophthalmic Solution is contraindicated in patients with hypersensitivity to apraclonidine or any other component of this medication, as well as systemic clonidine. It is also contraindicated in patients receiving monoamine oxidase inhibitors (MAO inhibitors).

Last updated on RxList: 1/24/2005

Apraclonidine hydrochloride is a relatively selective alpha-2-adrenergic agonist. When instilled in the eye, IOPIDINE 0.5% Ophthalmic Solution, has the action of reducing elevated, as well as normal, intraocular pressure (IOP), whether or not accompanied by glaucoma. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters.

Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. IOPIDINE 0.5% Ophthalmic Solution has the action of reducing IOP. The onset of action of apraclonidine can usually be noted within one hour, and maximum IOP reduction occurs about three hours after instillation. Aqueous fluorophotometry studies demonstrate that apraclonidine's predominant mechanism of action is reduction of aqueous flow via stimulation of the alpha-adrenergic system.

Repeated dose-response and comparative studies (0.125% - 1.0% apraclonidine) demonstrate that 0.5% apraclonidine is at the top of the dose/response IOP reduction curve.

The clinical utility of IOPIDINE 0.5% Ophthalmic Solution is most apparent for those glaucoma patients on maximally tolerated medical therapy. Patients on maximally tolerated medical therapy with uncontrolled IOP and scheduled to undergo laser trabeculoplasty or trabeculectomy surgery were enrolled into a double-masked, placebo-controlled, multi-center clinical trial to determine if IOPIDINE 0.5% Ophthalmic Solution, dosed three times daily (TID), could delay the need for surgery for up to three months.

All patients enrolled into this trial had advanced glaucoma and were undergoing maximally tolerated medical therapy, i.e., patients were using combinations of a topical beta blocker, sympathomimetics, parasympathomimetics and oral carbonic anhydrase inhibitors. Patients were considered to be treatment failures in this study if, in the opinion of the investigators, their IOP was uncontrolled by the masked study medication or there was evidence of further optic nerve damage or visual field loss, and surgery was indicated. Of 171 patients receiving masked medication, 84 were treated with IOPIDINE 0.5% Ophthalmic Solution and 87 were treated with placebo (apraclonidine vehicle).

Apraclonidine treatment resulted in a significantly greater percentage of treatment successes compared to patients treated with placebo. In this placebo-controlled maximum therapy trial, 14.3% of patients treated with IOPIDINE 0.5% Ophthalmic Solution were discontinued due to adverse events, primarily allergic-like reactions (12.9%).

The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in some patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a variable time of onset and should be closely monitored.

An unpredictable decrease of IOP control in some patients and incidence of ocular allergic responses and systemic side effects may limit the utility of IOPIDINE 0.5% Ophthalmic Solution. However, patients on maximally tolerated medical therapy may still benefit from the additional IOP reduction provided by the short-term use of IOPIDINE 0.5% Ophthalmic Solution.

Topical use of IOPIDINE 0.5% Ophthalmic Solution leads to systemic absorption. Studies of IOPIDINE 0.5% Ophthalmic Solution dosed one drop three times a day in both eyes for 10 days in normal volunteers yielded mean peak and trough concentrations of 0.9 ng/mL and 0.5 ng/mL, respectively. The half-life of IOPIDINE® 0.5% (apraclonidine ophthalmic solution) was calculated to be 8 hours.

IOPIDINE® 0.5% Ophthalmic Solution, because of its alpha adrenergic activity, is a vasoconstrictor. Single dose ocular blood flow studies in monkeys, using the microsphere technique, demonstrated a reduced blood flow for the anterior segment; however, no reduction in blood flow was observed in the posterior segment of the eye after a topical dose of IOPIDINE 0.5% Ophthalmic Solution. Ocular blood flow studies have not been conducted in humans.

Last updated on RxList: 1/24/2005

Do not touch dropper tip to any surface as this may contaminate the contents.

Last updated on RxList: 1/24/2005

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

APRACLONIDINE SOLUTION 0.5% - OPHTHALMIC

(ap-ruh-KLON-eh-deen)

COMMON BRAND NAME(S): Iopidine

USES: Apraclonidine is used along with other medications to treat serious high pressure inside the eye (glaucoma) for a short time (e.g., 1 month) to help delay or prevent the need for eye surgery. Decreasing high pressure inside the eye may help to prevent decreased vision or blindness. Apraclonidine is thought to work by decreasing the amount of fluid within the eye.

HOW TO USE: This medication is given as an eye drop, usually 3 times daily or as directed by your doctor.

If you are wearing contact lenses, remove them before using eye drops. Wait at least 15 minutes before replacing your contact lenses.

To apply eye drops, wash your hands first. To avoid contamination, be careful not to touch the dropper tip or let it touch your eye or any other surface.

Tilt your head back, look up, and pull down the lower eyelid to make a pouch. Hold the dropper directly over your eye and place 1 drop into the pouch. Release the eyelid and gently close your eyes. Place one finger at the corner of your eye (near the nose) and apply gentle pressure for 1 to 2 minutes. This will prevent the medication from draining out. Try not to blink and do not rub your eye. Repeat these steps for your other eye if so directed or if your dose is for more than 1 drop.

Remove extra solution around the eye with a tissue and wash your hands to remove any medicine that may be on them.

If you are using another kind of eye medication (e.g., drops or ointments), wait at least 5 minutes before using the other medication. Use eye drops before ointments to allow the eye drops to enter the eye.

Dosage is based on your medical condition and response to treatment. Do not increase your dose or use it more frequently than prescribed. When used for an extended time, this medication may not work as well and may require different dosing. Your doctor will monitor your progress with regular eye exams.

SIDE EFFECTS: Eye discomfort/redness/burning, blurred vision, dry mouth/nose, dizziness, drowsiness, upset stomach, or unusual tiredness may occur. Eye itching/watering or eyelid swelling may be symptoms of an allergic reaction of the eye. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., depression, irritability), slow/irregular heartbeat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using apraclonidine, tell your doctor or pharmacist if you are allergic to it; or to clonidine; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood vessel disease (e.g., cerebrovascular disease, Raynaud's disease), high blood pressure, heart problems (e.g., recent heart attack), kidney disease, mental/mood disorders (e.g., depression).

After you apply this drug, your vision may become temporarily blurred or unstable. It may also infrequently make you dizzy or drowsy. Use caution while driving, using machinery, or doing any other activity that requires alertness or clear vision. Limit alcoholic beverages.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before, during, and 2 weeks after taking this medication.

Before receiving this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: beta blockers (e.g., atenolol, metoprolol), high blood pressure medications, tricyclic antidepressants (e.g., amitriptyline, nortriptyline).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that may cause drowsiness. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medication may be harmful if swallowed. If swallowing or overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow heartbeat, drowsiness, cold/clammy skin.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., pulse, blood pressure, eye exams) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store between 36-80 degrees F (2-27 degrees C) away from light. Do not freeze. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.