Label: APRACLONIDINE OPHTHALMIC- apraclonidine hydrochloride solution/ drops

Rx only

Apraclonidine Ophthalmic Solution, USP 0.5% as base 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 C9H11Cl3N4 and a molecular weight of 281.57. The chemical structure of apraclonidine hydrochloride is:

Each mL of Apraclonidine Ophthalmic Solution, USP 0.5% as base contains:

Active: apraclonidine hydrochloride 5.75 mg equivalent to apraclonidine base 5 mg;

Inactives: sodium acetate, sodium chloride, sodium hydroxide and/or hydrochloric acid may be added to adjust pH (4.4 to 7.8) and water for injection;

Preservative: benzalkonium chloride 0.01%.

Apraclonidine hydrochloride is a relatively selective alpha-2-adrenergic agonist. When instilled in the eye, apraclonidine 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. Apraclonidine 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% to 1.0% apraclonidine) demonstrate that 0.5% apraclonidine is at the top of the dose/response IOP reduction curve.

The clinical utility of apraclonidine 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 apraclonidine ophthalmic solution, dosed three times daily, 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 apraclonidine 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 apraclonidine ophthalmic solution were discontinued due to adverse events, primarily allergic-like reactions (12.9%).

The IOP lowering efficacy of apraclonidine 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 apraclonidine ophthalmic solution. However, patients on maximally tolerated medical therapy may still benefit from the additional IOP reduction provided by the short-term use of apraclonidine ophthalmic solution.

Topical use of apraclonidine ophthalmic solution leads to systemic absorption. Studies of apraclonidine 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 apraclonidine ophthalmic solution was calculated to be 8 hours.

Apraclonidine 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 apraclonidine ophthalmic solution. Ocular blood flow studies have not been conducted in humans.

Apraclonidine Ophthalmic Solution, USP 0.5% as base 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 Apraclonidine Ophthalmic Solution, USP 0.5% as base to delay surgery should have frequent follow-up examinations and treatment should be discontinued if the intraocular pressure rises significantly.

The addition of Apraclonidine Ophthalmic Solution, USP 0.5% as base 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 Apraclonidine Ophthalmic Solution, USP 0.5% as base is an aqueous suppressing drug and the addition of a third aqueous suppressant may not significantly reduce IOP.

The IOP lowering efficacy of Apraclonidine Ophthalmic Solution, USP 0.5% as base 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.

Apraclonidine 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).

Not for injection or oral ingestion. FOR TOPICAL OPHTHALMIC USE ONLY.

In clinical studies the overall discontinuation rate related to apraclonidine 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 apraclonidine ophthalmic solution as being possibly, probably, or definitely related to therapy:

Ingestion of apraclonidine 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.

One to two drops of apraclonidine ophthalmic solution should be instilled in the affected eye(s) three times daily. Since apraclonidine 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.

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

Supplied in a white plastic LDPE ophthalmic bottle with a natural LDPE controlled dropper tip and a purple polypropylene cap as follows:

Principal Display Panel Text for Container Label

NDC 17478-716-10

0.5%

Apraclonidine

Ophthalmic

Solution, USP

0.5% as base

Sterile

Rx only 5 mL

Principal Display Panel Text for Carton Label

NDC 17478-716-10

Apraclonidine

Ophthalmic

Solution, USP

0.5% as base

FOR TOPICAL

OPHTHALMIC USE ONLY

5 mL

Sterile

Rx Only Akorn Logo