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 C 9 H 11 Cl 3 N 4 and a molecular weight of 281.57.
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%. Inactive: sodium chloride, sodium acetate, sodium hydroxide and/or hydrochloric acid (pH 4.4-7.8) and purified water.
Clinical Pharmacology: 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.
and Usage: 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.
Contraindications: 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).
: Not for injection or oral ingestion. Topical ophthalmic use only.
Precautions: 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 suggest 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' disease, or thromboangitis 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 thoses 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.
Patient Information: Do not touch dropper tip to any surface as this may contaminate the contents.
Drug Interactions: 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 Aproclonidine 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.
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.
Adverse Reactions: 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% Ophthalmic Solution therapy should be discontinued.
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:
Hyperemia (13%), pruritus (10%), discomfort (6%), tearing (4%). The following adverse reactions were reported in less than 3% of the patients: lid edema, blurred vision, foreign body sensation, dry eye, conjunctivitis, discharge, blanching. The following adverse reactions were reported in less than 1% of the patients: lid margin crusting, conjunctival follicles, conjunctival edema, edema, abnormal vision, pain, lid disorder, keratitis, blepharitis, photophobia, corneal staining, lid erythema, blepharoconjunctivitis, irritation, corneal erosion, corneal infiltrate, keratopathy, lid scales, lid retraction.
Body As A Whole: The following adverse reactions were reported in less than 3% of the patients: headache, asthenia. The following adverse reactions (incidences) were reported in less than 1% of the patients: chest pain, abnormal coordination, malaise, facial edema.
Cardiovascular: The following adverse reactions were reported in less than 1% of the patients: peripheral edema, arrhythmia. Although no reports of bradycardia related to IOPIDINE 0.5% Ophthalmic Solution were available from clinical studies, the possibility of its occurrence based on Apraclonidine's alpha-2-agonist effect should be considered (See Section).
Central Nervous System
The following adverse reactions were reported in less than 1% of the patients: somnolence, dizziness, nervousness, depression, insomnia, paresthesia.
Digestive System: Dry mouth (10%). The following adverse reactions were reported in less than 1% of the patients: constipation, nausea.
Musculoskeletal: Myalgia (0.2%).
Respiratory System: Dry nose (2%). The following adverse reactions were reported in less than 1% of the patients: rhinitis, dyspnea, pharyngitis, asthma.
Skin: The following adverse reactions were reported in less than 1% of the patients: contact dermatitis, dermatitis.
Special Senses: Taste perversion (3%), parosmia (0.2%).
Overdosage: While no instances of accidental or intentional ingestion of ophthalmic apraclonidine are known, 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, apnea, respiratory depression, hypoventilation, and seizure. 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.
Dosage and Administration: 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.
How Supplied: 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.
U.S. Patent No. 4,517,199