Apraclonidine is an imidazoline-derivative sympathomimetic amine.
Inhibition of Perioperative IOP Increases
In ophthalmology, topical apraclonidine 1% is used prophylactically before and after ocular laser surgery (e.g., argon laser trabeculoplasty, argon laser iridotomy, neodymium yttrium aluminum garnet [Nd:YAG] laser posterior capsulotomy) to prevent or reduce intraoperative and postoperative increases in intraocular pressure (IOP).1, 2, 16, 17, 18, 19, 20 Marked, transient acute increases in IOP occur frequently in untreated eyes undergoing laser procedures, particularly in eyes with preexisting glaucoma and in those receiving relatively large cumulative energy doses and/or laser pulses;2, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 37, 38, 39, 40, 41, 45, 46, 47 occasionally, increases may persist for prolonged periods after surgery (e.g., weeks to months).46 Such increases in IOP can result in visual field loss and optic nerve damage, especially in eyes with preexisting glaucoma.2, 18, 19, 22, 28, 30, 40, 45, 58, 59 Maximum increases in IOP usually occur about 1-4 hours after ocular laser surgery.18, 30, 45, 46, 59 The intraocular hypotensive effect of ophthalmic apraclonidine can reduce or prevent these adverse ocular effects in patients undergoing ocular laser procedures.1, 16, 17, 18, 19
Currently, methods for identifying factors that predispose to developing adverse ocular effects induced by increases in IOP have not been fully elucidated and prediction of which eyes will develop such effects following laser surgery cannot be made.2, 16, 17, 20, 40 However, the risk of visual field loss and optic nerve damage is greatest in patients with previously compromised optic nerves2, 22 and appears to increase in direct relation to the elevation of IOP associated with the laser surgical procedure.1, 2, 18, 28 In addition, patients with end-stage glaucoma and advanced visual field loss are at substantial risk, since acute increases in IOP in such patients potentially could destroy any remaining central vision.2, 39 It also appears that nonpseudophakic eyes are more likely than pseudophakic eyes to experience an IOP increase of more than 10 mm Hg.24
There currently is limited information available on the clinical use of topical apraclonidine for prevention or reduction of laser-induced perioperative increases in IOP in patients undergoing argon laser trabeculoplasty or iridotomy, or in patients undergoing Nd:YAG laser posterior capsulotomy.1, 2, 16, 17, 18, 19, 20, 58 In controlled studies in patients with preexisting glaucoma undergoing ocular laser surgical procedures, apraclonidine was more effective than placebo in reducing IOP 1-3 hours postoperatively.1, 2, 16, 17, 18, 19 IOP was reduced on average by about 1-4 mm Hg compared with presurgical values in eyes treated with apraclonidine and was increased on average by about 2.5-8.5 mm Hg in eyes treated with placebo.1, 16, 17, 18, 19 In these studies, 7% of eyes treated with single drops (as a 1% solution) of topical apraclonidine before and after laser surgery developed IOP elevations exceeding 5 mm Hg and 2% developed severe elevations (i.e., peak increases of 10 mm Hg or more) within the first 3 hours after surgery, while 32 and 23%, respectively, of eyes treated with placebo developed such elevations;1, 2, 16, 17, 18, 19 in most placebo-treated eyes that developed IOP elevations, peak postsurgical IOP exceeded 30 mm Hg and occasionally exceeded 50 mm Hg.1, 2, 16, 17, 18 In addition, only eyes treated with placebo required oral glycerin for reduction of IOP.16 In eyes undergoing iridotomy, there was no apparent difference in the ease of iridotomy formation or rate of iridotomy closure in those treated with topical apraclonidine compared with those treated with placebo.17
Although ophthalmic timolol18, 21, 24, 31 or pilocarpine21, 22, 23, 27 also has been used to reduce or prevent intraoperative increases in IOP in patients undergoing ocular laser surgery, the relative efficacy of apraclonidine compared with other ocular hypotensive agents in such patients remains to be fully elucidated.17, 18, 19 Limited data suggest, however, that apraclonidine may be more effective than these drugs in preventing or reducing laser-induced perioperative increases in IOP.2, 18, 58
Apraclonidine has been used topically in conjunction with pilocarpine, a β-adrenergic blocking agent (e.g., timolol), and/or a systemic carbonic anhydrase inhibitor prior to laser surgery;16, 17, 18 usually pilocarpine and/or the β-blocker were administered about 2-4 hours before and apraclonidine 1 hour before surgery.16, 17, 18 When apraclonidine is used in conjunction with other ocular hypotensive agents, additive IOP lowering may occur.16, 17, 58 Apraclonidine also has been used topically in conjunction with dexamethasone following surgery.16, 17, 18
Adjuvant Therapy for Reduction of IOP
Topical apraclonidine 0.5% is used for short-term adjunctive therapy in patients with glaucoma receiving maximally tolerated drug therapy who require additional reduction in intraocular pressure (IOP).62, 65 The addition of apraclonidine 0.5% ophthalmic solution to patients already receiving a topical β-adrenergic blocking agent in conjunction with a systemically administered carbonic anhydrase inhibitor, as components of maximally tolerated drug therapy, may not provide additional benefit for reduction of IOP, since addition of a third drug that also reduces aqueous humor formation may not further reduce IOP substantially.62, 65 Increases in IOP can result in visual field loss and optic nerve dama reduction in IOP may reduce or prevent glaucomatous visual field loss or optic nerve damage and delay or obviate surgery.1, 62, 66
Results of a placebo-controlled study in patients with advanced glaucoma receiving maximally tolerated drug therapy (i.e., those receiving a topical β-adrenergic blocking agent in conjunction with a systemically administered carbonic anhydrase inhibitor, and a sympathomimetic and/or a parasympathomimetic agent) who had uncontrolled IOP and were scheduled to undergo ocular laser surgery (i.e., argon laser trabeculoplasty) or trabeculectomy indicate that adjuvant therapy with topical apraclonidine 0.5% solution has delayed the need for surgery for up to 3 months in a greater percentage of patients than those receiving placebo (e.g., vehicle).62, 65 The greatest clinical benefit has been observed in patients with primary open-angle glaucoma and those with open-angle glaucoma associated with pigment dispersion.65
During continued therapy with topical apraclonidine 0.5%, tolerance to the effect in reducing IOP has been reported in some patients; the benefit for most patients receiving such therapy is less than 1 month.62, 65 In addition, since unpredictable decreases in control of IOP and development of ocular allergies and systemic adverse effects may occur in some patients receiving continued therapy with apraclonidine 0.5% ophthalmic solution, these effects may limit the benefit of such therapy.62 However, patients receiving maximally tolerated drug therapy may still benefit from the additional reduction of IOP provided by short-term administration of apraclonidine 0.5% ophthalmic solution.62
Results of several dose-response and comparative studies using apraclonidine 0.125-1% ophthalmic solution indicate that apraclonidine 0.5% solution is at the top of the IOP-lowering dose-response curve.62, 65 In a limited number of patients with open-angle glaucoma, apraclonidine hydrochloride 0.25 and 0.5% (of apraclonidine) applied topically to the eye at a dosage of 1 drop every 12 hours were similarly effective (although the reduction induced by the 0.5% solution persisted longer), producing mean maximal IOP reductions of about 27% (range: 18-64%). Maximum decreases in IOP in these patients occurred 2-5 hours after a dose of the drug.48 Apraclonidine increased the interpalpebral fissure width slightly, and had only a minimal mydriatic effect.48
Apraclonidine hydrochloride is applied topically to the eye as an ophthalmic solution.1, 2, 16, 17, 18, 19, 20, 54, 62 Care should be taken to avoid contamination of the solution container.34, 62 Apraclonidine hydrochloride ophthalmic solution is not for oral administration.62 In addition, the ophthalmic solution should not be injected into the eye.62
Although USP currently states that potency of apraclonidine hyrochloride preparations should be expressed both in terms of the salt and the base (“active moiety”),64 dosage currently is expressed in terms of the base.1 (See Chemistry and Stability: Chemistry.)
Inhibition of Perioperative IOP Increases
For the prevention or reduction of perioperative increases in intraocular pressure (IOP) in patients undergoing ocular laser surgery (e.g., argon laser trabeculoplasty, argon laser iridotomy), the usual dosage of apraclonidine is 1 drop of a 1% solution onto the eye undergoing surgery 1 hour before surgery and repeated immediately upon completion of surgery.1, 16, 17, 18, 19
Adjuvant Therapy for Reduction of IOP
When ophthalmic apraclonidine 0.5% is used for short-term adjunctive therapy in patients with glaucoma who are receiving maximally tolerated drug therapy and who require additional reduction in intraocular pressure (IOP), the usual dosage is 1 or 2 drops in the affected eye(s) 3 times daily.62, 65 Patients should be instructed that an interval of about 5 minutes is needed between administration of apraclonidine and other ophthalmic preparations in order to prevent loss of a previous dose.62, 65
Apraclonidine hydrochloride generally has been well tolerated following short-term (i.e., 1 drop of a 1% solution before and after surgery) topical application to the eye.1, 2, 16, 17, 18, 29, 36, 48 The most common adverse effects associated with continuous (for up to 12 weeks) topical application to the eye of the 0.5% solution are ocular allergic-like reactions including hyperemia, pruritus, tearing, ocular discomfort, foreign body sensation, and lid or conjunctival edema.62 During clinical trials, adverse effects requiring discontinuance of 0.5% apraclonidine therapy occur in about 15% of patients, principally for ocular allergic-like reactions.62, 65 These adverse effects usually were reversible upon discontinuance of the drug, did not require treatment, and did not result in sequelae.65 The adverse effect profile of the 0.5% ophthalmic solution when used for short-term therapy generally appeared to be similar to that observed when used for long-term (i.e., up to 12 months) therapy.65
Topical hypersensitivity to apraclonidine hydrochloride 0.5% (of apraclonidine) ophthalmic solution is the most frequent adverse effect reported with usual dosages (i.e., 1 or 2 drops instilled onto the eye[s] 3 times daily) of this preparation.62, 65 These allergic-like reactions include hyperemia in 13%, pruritus in 10%, ocular discomfort in 6%, tearing in 4%, lid edema or foreign body sensation in less than 3% of patients, and conjunctival edema in less than 1% of patients.62, 65 Other adverse ocular effects include dry eye, conjunctivitis, blurred vision, discharge, and blanching in less than 3% and lid margin crusting, lid erythema, lid scales, lid retraction, lid disorder, conjunctival follicles, edema, abnormal vision, pain, keratitis, keratopathy, blepharitis, blepharoconjunctivitis, photophobia, corneal staining, corneal erosion, corneal infiltrate, and irritation in less than 1% of patients receiving usual dosages of the 0.5% ophthalmic solution.62, 65
Topical hypersensitivity to apraclonidine hydrochloride 1% (of apraclonidine) ophthalmic solution also has been reported1, 36 and has been manifested as conjunctival hyperemia, eyelid swelling, and tearing.36 In at least one patient, hypersensitivity following topical application of the ophthalmic solution was evident about 9 hours after application and recurred at a similar time course following subsequent rechallenge.36
The most frequent adverse effects of topical apraclonidine hydrochloride 1% (of apraclonidine) with usual dosage (i.e., 1 drop of the solution instilled before and after surgery) in patients undergoing laser surgery are ocular injection,1 upper eyelid elevation,1, 2, 17, 19, 36 conjunctival blanching,1, 2, 19, 36 and mydriasis,1, 2, 36 occurring in about 0.4-1.8% of such patients.1, 2 Most of these effects are attributable to the drug's ocular α-adrenergic actions,2, 17, 19, 36 with eyelid elevation probably resulting from adrenergic stimulation of Müller's muscle17, 19, 36 and blanching probably resulting from decreased conjunctival blood flow.19, 36 Increased ocular inflammation, iridotomy closure, photopsia, focal corneal endothelial burns, and focal lens opacities also have been reported in patients undergoing laser surgery who received apraclonidine 1% ophthalmic solution;1, 19 however, these effects may be attributable to the laser procedure19, 30, 58 rather than the drug itself.58
When apraclonidine 1% was administered topically to the eye once or twice daily for 4 weeks in healthy individuals not undergoing laser surgery, the most common adverse ocular effects also were conjunctival blanching, upper eyelid elevation, and mydriasis.1, 2, 36 These effects reportedly occur in 5-9% of individuals receiving these dosages,1, 2 although frequencies for blanching and eyelid elevation of up to 85 and 50%, respectively, have been reported.36 The blanching, eyelid elevation, and mydriasis generally are apparent within 1 hour and maximal within 3-5 hours after application of the drug.36 Other adverse ocular effects included burning,1 discomfort,1, 48 foreign body sensation,1, 29, 48 tired eyes,1 dryness,1 itching,10 hypotony,1, 2, 29, 29 blurred or dimmed vision,1 and conjunctival microhemorrhage/erythema.1, 48 In one patient, ocular hypotony was manifested as a reduction in IOP from 11-12 to 4-5 mm Hg within 5-7 hours after application of a single drop of apraclonidine 1%;2, 29 the drug was discontinued without evidence of ocular sequelae.29 In these healthy individuals, there were no clinically important changes in basal tear secretion,2, 29 visual acuity,2, 29 visual field,2 pupillary diameter,2, 29 corneal sensitivity,2, 29 cup-to-disk ratio,2 or ocular motility.2
In rabbits, topical application to the eye of apraclonidine hydrochloride 0.5, 1, or 1.5% (of apraclonidine) at a dosage of 2 drops every 30 minutes for 6 hours resulted in a dose-related, mild to moderately severe ocular irritation 1 hour after the last dose.2, 65 Conjunctival changes in these rabbits included congestion, swelling, and dischar corneal changes included cloudiness and fluorescein staining; and pupillary changes included impaired light reflex.2, 65 Ocular irritation was of similar severity in rabbits receiving clonidine hydrocloride 0.5% (of clonidine) at the same frequency of administration, but was slightly less severe in rabbits receiving timolol maleate 0.5% (of timolol).2 Following topical application to the eye of 2 drops of apraclonidine hydrochloride 0.5 or 1% (of apraclonidine) 3 times daily for 1 month in rabbits, there was no evidence of toxic ocular effects, including necropsy findings, other than mild to moderately severe ocular irritation.2 However, transient, minimal corneal cloudiness, without histopathologic changes, was observed in a few rabbits when a 1.5% solution was applied at this frequency.1, 2 There was no evidence of corneal changes in monkeys receiving 2 drops of a 1.5% solution to the eye 3 times daily for 98 days1, 2 or in a study in humans who received at least 1 drop of a 1% solution of the drug.1 In the monkeys, sporadic, minimal conjunctival congestion was the only apparent adverse ocular effect.2
Perioperative use of apraclonidine hydrochloride ophthalmic solution to date has been associated with a low potential for causing adverse systemic effects;1, 2, 16, 17, 18, 19, 29, 36, 48 however, continuous (e.g., up to 12 weeks) use of apraclonidine ophthalmic solution has been associated with a higher incidence of systemic adverse effects.62
Following topical application to the eye at usual dosage (i.e., 1 drop of a 1% solution before and after surgery or 1 or 2 drops of a 0.5% solution administered up to 3 times daily), apraclonidine appears to produce little, if any, effect on systemic blood pressure1, 2, 15, 16, 19, 65 or heart rate;1, 2, 15, 16, 17, 18, 19, 65 however, irregular heart rate has been reported in less than 1% of patients receiving the drug.1 In general, apraclonidine appears to be less likely than clonidine to produce adverse systemic effects because of pharmacokinetic differences between the drugs (e.g., minimal CNS distribution of apraclonidine).2, 19, 29, 36, 61, 65 However, such effects occasionally have occurred in individuals receiving ophthalmic apraclonidine.1, 2, 29 A vasovagal attack occurred in at least one patient receiving usual dosage of the drug; however, the attack may have been precipitated by perioperative anxiety, and a causal relationship to apraclonidine was not established.2, 17
When apraclonidine 1% was administered topically to the eye once or twice daily for 4 weeks in healthy individuals not undergoing laser surgery, there were occasional reports of bradycardia,1, 29 chest heaviness or burning,1 palpitation,1 reduced systolic and diastolic blood pressures,2, 29 and orthostatic hypotension.1, 57 In these individuals, maximum diastolic blood pressure reductions averaged about 6% of baseline values and generally were not considered clinically important, although reductions exceeding 20% occurred occasionally.29 Pulse rate decreased by an average of 6 beats per minute after 8 days of administration but ranged from a 42% decrease to a 44% increase overall during 4 weeks of administration.2, 29 Following topical application of usual (1 or 2 drops in the eye[s] 3 times daily) dosages of apraclonidine 0.5% ophthalmic solution, peripheral edema and arrhythmia were reported in less than 1% of patients.62, 65
While adverse GI effects appear to be uncommon with usual dosage of apraclonidine 1% ophthalmic solution (i.e., 1 drop before and after surgery),1, 2, 16, 17, 18, 19 such effects may occur commonly with more frequent and/or prolonged administration of the drug.1, 2, 29, 48 Nasal decongestion has been reported in less than 1% of patients receiving the drug before and after laser surgery.1 When apraclonidine 0.125-1% was administered topically to the eye 1-3 times daily for 1-12 weeks in healthy individuals1, 2, 29 or patients with open-angle glaucoma48, 54, 57, 62 not undergoing laser surgery, the most common adverse GI effects were dry or burning mouth and/or nose1, 2, 29, 48, 62 and dysgeusia.1, 2, 48, 62 Dry mouth and/or nose occurred in up to 57% of those receiving a 1% solution, being most common during the first 1-2 weeks of administration, but generally were well tolerated and gradually diminished in frequency and severity during continued use of the drug.29 Dry mouth and dry nose have been reported in 10 and 2% of patients receiving the 0.5% solution, respectively.62, 65 Dysgeusia reportedly occurred in 3% of those receiving a 0.5 or 1% solution.2, 62 Other adverse GI effects associated with administration of the 1% solution include abdominal pain,1 diarrhea,1 gastric discomfort,1 nausea,29 dyspepsia,29 and vomiting.1 In addition, constipation and nausea were reported in less than 1% of patients receiving the 0.5% solution.62, 65
Adverse nervous system effects appear to be uncommon with usual dosage of apraclonidine (i.e., 1 drop of a 1% solution before and after surgery);1, 2, 16, 17, 18, 19 however, such effects appear to be common at higher dosages.1, 29, 48 When apraclonidine 0.125-1% was administered topically to the eye 1-3 times daily for 1-12 weeks in healthy individuals1, 29 or in patients with open-angle glaucoma48, 57, 62 not undergoing laser surgery, lethargy1, 29, 48 was reported in up to 14% of individuals.29, 48 Adverse nervous system effects reported less frequently included insomnia,1, 62, 65 dream disturbances,1 irritability,1 somnolence,62, 65 dizziness,62 nervousness,62, 65 depression,62, 65 asthenia,62 headache,1, 62 fatigue,1 paresthesia,1, 62, 65 numbness or pain of the extremities,1, 48 and decreased libido.1
Other Adverse Systemic Effects
When apraclonidine 1% was administered topically to the eye once or twice daily for 4 weeks in healthy individuals not undergoing laser surgery, other adverse systemic effects included clammy or sweaty palms,1 head-cold sensation,1 shortness of breath,1 flushing or heat sensation,1 increased pharyngeal secretion,1 and pruritus without rash.1 In patients with glaucoma receiving apraclonidine 0.5%, rhinitis, dyspnea, pharyngitis, parosmia, asthma, dermatitis (including contact dermatitis), chest pain, abnormal coordination, malaise, facial edema, and myalgia have been reported in less than 1% of patients.62, 65
Precautions and Contraindications
Apraclonidine appears to have a low potential for adverse systemic effects when applied topically to the eye at usual perioperative dosage (i.e., 1 drop of a 1% solution before and after surgery);1, 2, 16, 17, 18, 19 however, the possibility that such effects could occur even at this dosage should be considered.1, 2, 15, 19 More frequent and/or prolonged administration of apraclonidine ophthalmic solutions has been associated with a higher incidence of systemic adverse effects.1, 18, 29, 36, 62 While topical application of the drug to the eye appears to cause minimal alterations in systemic blood pressure or heart rate (see Cautions: Systemic Effects), 1, 2, 15, 16, 17, 18, 19, 36, 48, 65 ophthalmic apraclonidine should be used with caution in patients with severe uncontrolled cardiac disease, including hypertension.1, 62, 65 Although bradycardia has not been reported to date in patients receiving continuous therapy with apraclonidine 0.5% ophthalmic solution, the possibility of such an adverse effect should be considered due to the drug's α2-adrenergic agonist activity.62
The manufacturer states that ophthalmic apraclonidine should be used with caution in patients with coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, Raynaud's disease, or thromboangiitis obliterans.62 Ophthalmic apraclonidine also should be used with caution in patients with depression, since the drug rarely has been associated with depression.62 Since topical apraclonidine may cause dizziness and somnolence, patients receiving the drug should be cautioned that apraclonidine may impair their ability to perform hazardous activities requiring mental alertness.62
Apraclonidine ophthalmic solution has been associated with development of ocular allergic-like reactions including hyperemia, pruritus, tearing, ocular discomfort, foreign body sensation, and lid or conjunctival edema; if such ocular symptoms occur topical apraclonidine therapy should be discontinued.62
Efficacy of topical apraclonidine 0.5% may diminish during therapy.62 Because tachyphylaxis is subject to individual variation, patients should be monitored closely.62 In addition, since unpredictable decreases in control of IOP and development of ocular allergies and systemic adverse effects may occur in some patients receiving continued therapy with apraclonidine 0.5% ophthalmic solution, these effects may limit the benefit of such therapy.62 However, patients receiving maximally tolerated drug therapy may still benefit from the additional reduction of IOP provided by short-term administration of apraclonidine 0.5% ophthalmic solution.62
The manufacturer states that topical apraclonidine also should be used with caution in patients with a history of vasovagal attacks1 since such attacks may occur during laser surgery in these patients;1, 17 however, some clinicians question the rationale for this precaution.58
Because apraclonidine is a potent depressor of intraocular pressure (IOP), patients who develop excessive IOP reduction should be monitored closely.1 Visual field tests should be performed periodically in patients who are receiving maximally tolerated drug therapy for advanced glaucoma and who also are receiving apraclonidine ophthalmic solution 0.5% to delay surgery.62 These patients also should have frequent follow-up examinations; topical apraclonidine therapy should be discontinued if IOP increases substantially.62
Although topical apraclonidine has not been studied in patients with renal impairment (e.g., renal failure), the half-life of clonidine is increased substantially in patients with severe renal impairment, therefore, cardiovascular parameters should be monitored closely in patients with severe renal impairment who are receiving topical apraclonidine therapy.62 In addition, since clonidine is partially metabolized in the liver, patients with hepatic impairment receiving topical apraclonidine therapy also should be monitored closely.62
Ophthalmic apraclonidine is contraindicated in patients with known hypersensitivity to apraclonidine, clonidine, or any ingredient in the formulation.1, 62 Apraclonidine ophthalmic solution also is contraindicated in patients receiving a monoamine oxidase (MAO) inhibitor.62
Safety and efficacy of apraclonidine hydrochloride ophthalmic solution in children younger than 21 years of age have not been established.1, 57
Mutagenicity and Carcinogenicity
No evidence of apraclonidine-induced mutagenicity was seen with in vitro microbial (Ames test), or malignant aberration test systems.1, 2, 62, 65 Apraclonidine also was inactive in the mouse lymphoma cell forward mutation and Chinese hamster ovary chromosome aberration assays, in the sister chromatid exchange assay in Chinese hamster ovary cells, and in a cell transformation assay.62, 65 No evidence of apraclonidine-induced mutagenic activity was seen with an in vivo mouse micronucleus test.62, 65
No substantial differences in tumor incidence or type occurred in rats receiving oral dosages of 1 mg (of apraclonidine)/kg daily (about 20 times the maximum human ocular dosage) for 2 years or in mice receiving oral dosages of 0.6 mg/kg daily (about 12 times the maximum human ocular dosage) for 2 years.57, 62
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans, apraclonidine has been shown to have embryocidal effects in rabbits receiving oral dosages of 3 mg/kg (about 60 times the maximum recommended human dose) daily.62 In rats, apraclonidine caused dose-related maternal toxicity with oral dosages of 0.3 mg/kg daily (about 6 times the maximum recommended human dosage).62 It is not known whether the drug can cause fetal harm when administered as an ophthalmic solution to pregnant women.1 Ophthalmic apraclonidine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 62
Reproduction studies in male and female rats using oral apraclonidine dosages of 0.5 mg/kg daily (about 5-10 times the maximum recommended human dosage) for 10 and 2 weeks prior to breeding, respectively, have not revealed evidence of impaired fertility.62, 65 It is not known whether the drug can adversely affect fertility when administered as an ophthalmic solution.1
It is not known whether apraclonidine is distributed into milk.1, 62 Because many drugs are distributed into milk, apraclonidine 0.5% ophthalmic solution should be used with caution in nursing women.62 If apraclonidine 1% ophthalmic solution is used for inhibition of perioperative intraocular pressure (IOP) increases, the need to discontinue nursing temporarily during the day that apraclonidine is used should be considered.1
The potential interactions between apraclonidine hydrochloride ophthalmic solution and other ophthalmic drugs have not been fully evaluated.1 However, the manufacturer states that topical apraclonidine should not be used in patients receiving a monoamine oxidase (MAO) inhibitor.62 In addition, although no drug interactions have been reported in clinical studies in patients with glaucoma receiving topical apraclonidine concomitantly with topical or systemic drugs, the manufacturer states that the possibility of additive CNS effects should be considered when topical apraclonidine is administered concomitantly with CNS depressants such as barbiturates, opiates, anesthetics, sedatives, or alcohol.62 Tricyclic antidepressants have blunted the hypotensive effects of systemically administered clonidine, and it is not known if concurrent use of tricyclic antidepressants with topical apraclonidine may decrease the IOP-lowering effect of the drug.62 No data is available on the circulating plasma concentrations of catecholamines following apraclonidine withdrawal; however, the manufacturer states that caution should be exercised in concomitant use of drugs (e.g., tricyclic antidepressants) that affect the metabolism or tissue uptake of these amines.62 It should be considered that systemically administered clonidine and antipsychotic drugs appear to have additive hypotensive effects.62 Also, the manufacturer cautions that systemically administered clonidine may inhibit production of catecholamines in response to insulin-induced hypoglycemia and mask signs and symptoms of hypoglycemia.62
Since apraclonidine may decrease heart rate and blood pressure, the drug should be used with caution in patients receiving antihypertensive agents, cardiac glycosides, topically or systemically administered β-adrenergic blocking agents, or similar pharmacologic agents.62 The manufacturer states that pulse and blood pressure should be monitored frequently in patients receiving topical apraclonidine concomitantly with cardiac drugs.62 Limited data indicate that when apraclonidine hydrochloride ophthalmic solution is used in conjunction with a topical β-adrenergic blocking agent (e.g., timolol) or pilocarpine, the drugs may have an additive IOP-lowering effect.16, 17
The oral LD50 of apraclonidine hydrochloride is 3-8 and 38-107 mg/kg in mice and rats, respectively,1, 2, 65 and the IV LD50 of the drug is 6-9 and 9-21 mg/kg in mice and rats, respectively.1, 2, 65 These LD50 values indicate that the toxic potential of apraclonidine is high.1, 2
While there currently is no information available on ocular or oral overdosage of apraclonidine in humans,1 signs and symptoms of overdosage of oral clonidine, which is structurally and pharmacologically related to apraclonidine, include hypotension, transient hypertension, weakness, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, sedation or coma, skin pallor, hypothermia, decreased heart rate, cardiac conduction defects, arrhythmias, dryness of the mouth, miosis, apnea, respiratory depression, hypoventilation, and seizures.1, 62 If such symptoms occur, supportive and symptomatic treatment should be initiated and an adequate airway established.1, 62 Hemodialysis is of limited value in the treatment of clonidine overdosage, since a maximum of 5% of circulating drug is removed.62 (See Acute Toxicity: Treatment, in Clonidine 24:24.)
Apraclonidine, like clonidine,2, 4, 6, 11, 12, 13, 49 is a relatively selective α2-adrenergic agonist.1, 4, 7, 12, 19, 43, 62, 65 However, this selectivity for α2-receptors is not absolute and apraclonidine also may stimulate, to a lesser extent, α1-receptors.2, 13 It is believed that α2-adrenergic effects result from inhibition of the production of cyclic adenosine monophosphate (AMP) by inhibition of adenylate cyclase.4, 6, 13, 43 In vitro studies indicate that the α2-adrenergic agonist activity of apraclonidine on a molar basis is approximately 2-15 times that of clonidine.4, 11, 12, 13 It has been postulated that clonidine and apraclonidine may behave as partial α2-receptor agonists, their effects depending on the endogenous concentration of norepinephrine.3, 4, 5, 49 At low norepinephrine concentrations, the drugs may cause α-adrenergic stimulation,3, 4, 5 while the drugs may cause α2-adrenergic antagonism when norepinephrine concentrations are high.3, 4, 5, 49
Following topical application to the eye, apraclonidine reduces both elevated1, 16, 17, 18, 19, 48, 54, 62, 65 and normal2, 29, 36, 62, 65 intraocular pressure (IOP) in patients with or without glaucoma.1, 16, 17, 18, 19, 48, 54 In animals, apraclonidine reduces laser- or steroid-induced elevations in IOP by about 23-44%.2, 33, 61 The drug also has been shown to prevent or reduce IOP elevations induced by laser surgery in humans, producing IOP reductions of about 17-26% from preoperative values.16, 17, 18, 19 Apraclonidine also reduces IOP in healthy individuals, producing reductions averaging about 23-39% from baseline,2, 29, 48 although in some studies in healthy animals substantially smaller reductions in IOP were observed.33, 61
The reduction in IOP induced by α2-adrenergic agonists may result from both peripheral (e.g., local)2, 3, 8, 9, 10, 56, 61 and central3, 8, 9, 10, 50, 51, 52, 53, 58, 60, 61 effects. However, because apraclonidine distributes across the ocular-blood barrier2 and into the CNS less effectively than clonidine,2, 32, 33, 61, 65 it is likely that topical apraclonidine reduces IOP principally via a peripheral action.2, 61 The exact mechanism(s) of action by which apraclonidine and clonidine reduce IOP has not been clearly established,1, 3, 8, 9, 10, 19, 56, 65 but fluorophotometric studies suggest that reduced aqueous humor formation, via α-adrenergic stimulation, is the predominant effect.1, 3, 10, 19, 55, 56, 62, 65 It has been postulated that constriction of afferent ciliary process vessels is the principal mechanism for reduced aqueous humor formation induced by these drugs.2, 3, 10, 53, 56 However, it also has been suggested that the ocular hypotensive action of α2-adrenergic agonists may result, at least in part, from a centrally mediated inhibition of adrenergic vasoconstriction in the eye,3, 8, 9, 10, 50, 51, 52, 53, 58, 60, 61 although it is unlikely that this effect contributes substantially to apraclonidine-induced reductions in IOP.58, 60 Although limited evidence indicates that apraclonidine does not appear to affect aqueous humor outflow facility substantially,2, 36 further studies are needed to evaluate the potential effects of the drug on outflow facility, especially in patients with elevated IOP and glaucoma.2
There is some evidence that apraclonidine also may reduce IOP in the contralateral, untreated eye, although to a lesser extent than in the treated eye.2, 36 In many patients, however, no appreciable reduction of IOP in the untreated eye is observed.16, 17, 19
Topically applied apraclonidine produces local vasoconstriction and reduction in blood flow by its effect on α-adrenergic receptors.2, 33, 62 The drug constricts anterior conjunctival vessels and adnexal ocular tissues and reduces blood flow in anterior eye structures;2, 33, 36, 60 this effect may be manifested as conjunctival blanching.36 Although limited animal data suggest that apraclonidine may not affect blood flow to the retina or optic nerve,2, 33 additional study is necessary to fully elucidate the effects of the drug on blood flow in these regions.7, 53, 58
Apraclonidine produces substantial mydriasis in rabbits and cats, but only minimal mydriasis in monkeys.2, 33 Equivocal effects on pupillary diameter have been observed in humans,16, 29, 36, 48 although it has been suggested that mydriasis may become increasingly apparent as apraclonidine dosage is increased.48, 58 Changes in visual acuity have not been observed with topical apraclonidine,16, 17, 29 and the drug appears to have minimal local anesthetic effect on the cornea.1, 29
Ophthalmic apraclonidine appears to lower blood pressure and heart rate to a lesser extent than ophthalmic clonidine.2, 14, 15, 17, 19, 29, 36, 61, 65 (See Cautions: Systemic Effects.) These differences probably result from decreased distribution of apraclonidine across the ocular-blood barrier2, 65 and into the CNS2, 32, 33, 61 compared with that of clonidine. Likewise, apraclonidine appears to have minimal potential for causing sedation and other nervous system effects,2, 29, 33, 61 although such effects can occur.1, 2, 29, 62 (See Cautions: Systemic Effects.)
At relatively high concentrations in vitro, apraclonidine can inhibit epinephrine-induced platelet aggregation;13 the relevance of this finding to ocular platelet aggregation in vivo is not known.57, 58
In all studies described in the Pharmacokinetics section, apraclonidine was administered as the hydrochloride salt; dosages and concentrations of the drug are expressed in terms of apraclonidine.57
Some systemic absorption of apraclonidine hydrochloride occurs following topical application to the eyes and systemic effects (e.g., reduction in heart rate, reduction in blood pressure) occasionally have been reported following topical application of the drug.1, 2, 15, 29, 62 Because apraclonidine is substantially less lipophilic than clonidine, apraclonidine crosses the ocular-blood barrier much less readily than clonidine following topical application to the eye, with resultant systemic absorption being less with apraclonidine.2, 61, 65
Following topical application of 1 drop of a 0.5% solution of apraclonidine hydrochloride to both eyes 3 times daily for 10 days in healthy adults, mean peak and trough plasma apraclonidine concentrations reportedly were 0.9 and 0.5 ng/mL, respectively.62, 65 Following topical application to the eye of a 1% solution of apraclonidine, reduction in IOP usually is evident within 1 hour, reaches a maximum within about 3-5 hours, and persists for at least 12 hours.1, 2, 16, 17, 62
Distribution of apraclonidine hydrochloride into human ocular tissues and fluids has not been characterized to date.57 In addition, distribution of the drug into human body tissues and fluids following systemic absorption has not been characterized.57 Following IV administration of apraclonidine hydrochloride in rats, the drug is distributed only minimally into the CNS.2, 32, 33
It is not known whether apraclonidine hydrochloride is distributed into milk1, 57, 62 or crosses the placenta.57
The metabolic fate and elimination characteristics of apraclonidine hydrochloride have not been fully elucidated.57, 58, 62 Following ocular instillation of 1 drop of apraclonidine 0.5% ophthalmic solution into both eyes 3 times daily for 10 days in healthy individuals, the elimination half-life of the drug is calculated to be 8 hours.62, 65
Apraclonidine is a relatively selective α2-adrenergic agonist.1, 4, 7, 12, 19, 29, 62, 65 Apraclonidine is an imidazoline-derivative sympathomimetic amine.1, 2, 3, 62 The drug is structurally and pharmacologically related to clonidine,1, 2, 4, 61, 65 differing only by the addition of an amino group at the para position of imidazolidine.1, 2, 4, 61, 65 The drug also is structurally related to naphazoline, oxymetazoline, tetrahydrozoline, and xylometazoline.3
Apraclonidine hydrochloride occurs as a white to off-white powder1, 62 and has approximate solubilities of 29 mg/mL in water and 13.6 mg/mL in alcohol at 25°C.57 The drug has a pKa of 9.22.57 Because of differences in pKa, apraclonidine is more highly ionized at physiological pH than is clonidine.2 Each 5.75 mg of apraclonidine hydrochloride is equivalent to about 5 mg of apraclonidine.1, 62, 65
USP currently states that potency of apraclonidine hydrochloride preparations should be expressed both in terms of the salt and the base (“active moiety”).64 Previously, potency was expressed only in terms of apraclonidine base. Dosage currently continues to be expressed in terms of the base.1, 62 Therefore, care should be taken to avoid confusion between labeled potencies as the salt and base and dosage of apraclonidine hydrochloride.63
Apraclonidine hydrochloride ophthalmic solution is a sterile, isotonic solution of the drug in purified water;1, 62 sodium acetate, hydrochloric acid, and/or sodium hydroxide are added to adjust pH to 4.4-7.8.1, 62, 64, 65 The ophthalmic solution also contains benzalkonium chloride as a preservative and sodium chloride to adjust tonicity.1, 62, 65
Apraclonidine hydrochloride ophthalmic solutions should be stored in tight, light-resistant containers;1, 62, 64, 65 apraclonidine 0.5% ophthalmic solution should be stored at 2-27°C and protected from freezing, while apraclonidine 1% ophthalmic solution should be stored at room temperature.1, 62, 65
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Solution | 0.5% (of apraclonidine) | Iopidine® (with benzalkonium chloride) | Alcon |
1% (of apraclonidine) | Iopidine® (with benzalkonium chloride) | Alcon |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Alcon Laboratories. Iopidine® (apraclonidine hydrochloride) 1% prescribing information. Fort Worth, TX; 1995 Sep.
2. Alcon Laboratories. Iopidine ® product monograph. Fort Worth, TX; 1988 Feb.
3. Havener WH. Ocular pharmacology. 5th ed. St. Louis: The CV Mosby Co.; 1983:262-417.
4. Atlas D, Sabol SL. Interaction of clonidine and clonidine analogues with α-adrenergic receptors of neuroblastoma × glioma hybrid cells and rat brain. Eur J Biochem . 1981; 113:521-9. [PubMed 6260485]
5. Rudd P, Blaschke T. Antihypertensive agents and the drug therapy of hypertension. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:784-805.
6. Weiner N, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:66-99.
7. Forster BA, Ferrari-Dileo G, Anderson DR. Adrenergic alpha1 and alpha2 binding sites are present in bovine retinal blood vessels. Invest Ophthalmol Vis Sci . 1987; 28:1741-6. [PubMed 3667146]
8. Harrison R, Kaufmann CS. Clonidine: effects of a topically administered solution on intraocular pressure and blood pressure in open-angle glaucoma. Arch Ophthalmol . 1977; 95:1368-73. [PubMed 889511]
9. Krieglstein GK, Langham ME, Leydhecker W. The peripheral and central neural actions of clonidine in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci . 1978; 17:149-58. [PubMed 24018]
10. Macri FJ, Cevario SJ. Clonidine: effects on aqueous humor formation and intraocular pressure. Arch Ophthalmol . 1978; 96:2111-3. [PubMed 718505]
11. Rouot BR, Snyder SH. [3H]Para-Amino-clonidine: a novel ligand which binds with high affinity to α-adrenergic receptors. Life Sci . 1979; 25:769-74. [PubMed 40089]
12. Sripanidkulchai B, Dawson R, Oparil S et al. Two renal α2-adrenergic receptor sites revealed by p -aminoclonidine binding. Am J Physiol . 1987; 252:(2 Part 2):F283-90.
13. Stump DC, Macfarlane DE. Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets. J Lab Clin Med . 1983; 102:779-87. [PubMed 6138385]
14. Hodapp E, Kolker AE, Kass MA et al. The effect of topical clonidine on intraocular pressure. Arch Ophthalmol . 1981; 99:1208-11. [PubMed 7020658]
15. Hernandez Y, Hernandez H, Cervantes R, Frati A et al. J. Toxicol. 1983; 2:99-106.
16. Robin AL, Pollack IP, House B et al. Effects of ALO 2145 on intraocular pressure following argon laser trabeculoplasty. Arch Ophthalmol . 1987; 105:646-50. [PubMed 2887153]
17. Robin AL, Pollack IP, deFaller JM. Effects of topical ALO 2145 ( p -aminoclonidine hydrochloride) on the acute intraocular pressure rise after argon laser iridotomy. Arch Ophthalmol . 1987; 105:1208-11. [PubMed 3307717]
18. Pollack IP, Brown RH, Crandall AS et al. Prevention of the rise in intraocular pressure following neodymium-YAG posterior capsulotomy using topical 1% apraclonidine. Arch Ophthalmol . 1988; 106:754-7. [PubMed 3369999]
19. Brown RH, Stewart RH, Lynch MG et al. ALO 2145 reduces the intraocular pressure elevation after anterior segment laser surgery. Ophthalmology . 1988; 95:378-384. [PubMed 3050686]
20. Fourman S. Effects of topical ALO 2145 ( p -aminoclonidine hydrochloride, aplonidine hydrochloride) on the acute intraocular pressure rise after argon laser iridotomy. Arch Ophthalmol . 1988; 106:307-9. [PubMed 3345140]
21. Henry JC, Krupin T, Schultz J et al. Increased intraocular pressure following neodymium-YAG laser iridectomy. Arch Ophthalmol . 1986; 104:178. [PubMed 3753864]
22. Brown SVL, Thomas JV, Belcher CD III et al. Effect of pilocarpine in treatment of intraocular pressure elevation following neodymium: YAG laser posterior capsulotomy. Ophthalmology . 1985; 92:354-9. [PubMed 3991123]
23. Ofner S, Samples JR, Van Buskirk EM. Pilocarpine and the increase in intraocular pressure after trabeculoplasty. Am J Ophthalmol . 1984; 97:647-9. [PubMed 6720849]
24. Migliori ME, Beckman H, Channell MM. Intraocular pressure changes after neodymium-YAG laser capsulotomy in eyes pretreated with timolol. Arch Ophthalmol . 1987; 105:473-475. [PubMed 3566598]
25. Weinreb RN, Robin AL, Baerveldt G et al. Flurbiprofen pretreatment in argon laser trabeculoplasty or primary open-angle glaucoma. Arch Ophthalmol . 1984; 102:1629-32. [PubMed 6497745]
26. Ruderman JM, Zweig KO, Wilensky JT et al. Effects of corticosteroid pretreatment on argon laser trabeculoplasty. Am J Ophthalmol . 1983; 96:84-9. [PubMed 6869482]
27. Schrems W, Eichelbronner O, Krieglstein GK. The immediate IOP response of Nd-YAG-laser iridotomy and its prophlactic treatability. Acta Ophthalmol . 1984; 62:673-80.
28. Weinreb RN, Ruderman J, Juster R et al. Immediate intraocular pressure response to argon laser trabeculoplasty. Am J Ophthalmol . 1983; 95:279-86. [PubMed 6829673]
29. Abrams DA, Robin AL, Pollack IP et al. The safety and efficacy of topical 1% ALO 2145 ( p -aminoclonidine hydrochloride) in normal volunteers. Arch Ophthalmol . 1987; 105:1205-1207. [PubMed 3307716]
30. Stark WJ, Worthen D, Holladay JT et al. Neodymium:YAG lasers: an FDA report. Ophthalmology . 1985; 92:209-12. [PubMed 3982799]
31. Richter CV, Arzeno G, Pappas HR et al. Prevention of intraocular pressure elevation following neodymium-YAG laser posterior capsulotomy. Arch Ophthalmol . 1985; 103:912-5. [PubMed 3839390]
32. Cavero I, Depoortere H, LeFevre-Borg F. Pharmacological studies on para-aminoclonidine. Br J Pharmacol . 1980; 69:295P-6.
33. Chandler ML, DeSantis L. Studies of p -amino clonidine as a potential antiglaucoma agent. Invest Ophthalmol Vis Sci . 1985; 25(Suppl):227.
34. American Society of Health-System Pharmacists, Inc.. Medication teaching manual: a guide for patient counseling. 2nd ed: Bethesda, MD: American Society of Hospital Pharmacists; 1980: 300.
35. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore, MD: Williams & Wilkins; 1984:I-6.
36. Robin AL. Short-term effects of unilateral 1% apraclonidine therapy. Arch Ophthalmol . 1988; 106:912-5. [PubMed 3390053]
37. Moster M, Simmons S, Feldman R et al. Cyclocryotherapy: acute intraocular pressure rise and long term results. Invest Ophthalmol Vis Sci . 1987; 28(Suppl):273.
38. Hoskins HD, Hetherington J Jr, Minckler DS et al. Complications of laser trabeculoplasty. Ophthalmology . 1983; 90:796-9. [PubMed 6622019]
39. Thomas JV, Simmons RJ, Belcher CD III. Argon laser trabeculoplasty in the presurgical glaucoma patient. Ophthalmology . 1982; 89:187-97. [PubMed 7088501]
40. Krupin T, Stone RA, Cohen BH et al. Acute intraocular pressure response to argon laser iridotomy. Ophthalmology . 1985; 92:922-6. [PubMed 4022578]
41. Robin AL, Pollack IP. A comparison of neodymium: YAG and argon laser iridotomies. Ophthalmology . 1984; 91:1011-6. [PubMed 6387569]
42. Wise JB, Witter SL. Argon laser therapy for open-angle glaucoma: a pilot study. Arch Ophthalmol . 1979; 97:319-22. [PubMed 575877]
43. Simmons RMA, Jones DJ. Binding of [3H]prazosin and [3H] p -aminoclonidine to α-adrenoceptors in rat spinal cord. Brain Res . 1988; 445:338-49. [PubMed 2836025]
44. Petursson G, Cole R, Hanna C. Treatment of glaucoma: using minidrops of clonidine. Arch Ophthalmol. 1984;102:1180-1. [PubMed 6380466]
45. Flohr MJ, Robin AL, Kelley JS. Early complications following Q-switched neodymium:YAG laser posterior capsulotomy. Ophthalmology . 1985; 92:360-3. [PubMed 3991124]
46. Channell MM, Beckman H. Intraocular pressure changes after neodymium-YAG laser posterior capsulotomy. Arch Ophthalmol . 1984; 102:1024-6. [PubMed 6547596]
47. Pollack IP, Patz A. Argon laser iridotomy: an experimental and clinical study. Ophthalmol Surg . 1976; 7:22-30.
48. Jampel HD, Robin AL, Quigley HA et al. Apraclonidine: a one-week dose-response study. Arch Ophthalmol . 1988; 106:1069-73. [PubMed 3041944]
49. Lowenstein J. Drugs five years later: clonidine. Ann Intern Med . 1980; 92:74-7. [PubMed 6101302]
50. Innemee HC, van Zwieten PA. The central ocular hypotensive effect of clonidine. Albrecht von Graefes Arch Ophthalmol . 1979; 210:93-102.
51. Innemee HC, Hermans AJ, van Zwieten PA. The influence of clonidine on intraocular pressure after topical application to the eyes of anesthetized cats. Albrecht von Graefes Arch Ophthalmol . 1979; 212:19-27.
52. Liu JH, Neufeld AH. Study of central regulation of intraocular pressure using ventriculocisternal perfusion. Invest Ophthalmol Vis Sci . 1985; 26:136-43. [PubMed 4038694]
53. Bill A, Heilmann K. Ocular effects of clonidine in cats and monkeys. Exp Eye Res . 1975; 21:481-8. [PubMed 812714]
54. Morrison JC, Robin AL. Adjunctive glaucoma therapy: a comparison of apraclonidine and dipivefrin when added to timolol maleate. Ophthalmology . (in press).
55. Gharagozloo NZ, Relf SJ, Brubaker RF. Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO 2145). Ophthalmology . 1988; 95:1217-20. [PubMed 3062536]
56. Lee DA, Topper JE, Brubaker RF. Effect of clonidine on aqueous humor flow in normal human eyes. Exp Eye Res. 1984; 38:239-46.
57. Alcon Laboratories, Fort Worth, TX: Personal communication.
58. Reviewers' comments (personal observations); 1988 Oct.
59. Vine AK. Ocular hypertension following Nd:YAG laser capsulotomy: a potentially blinding combination. Ophthalmic Surg . 1984; 15:283-4. [PubMed 6547221]
60. Innemee HC, van Zwieten PA. The distribution in the eye and the effect on intraocular pressure of clonidine. Albrecht von Graefes Arch Ophthalmol . 1979; 209:189-98.
61. York BM Jr, inventor; Alcon Laboratories Inc, assignee. Method for lowering intraocular pressure using phenylimino-imidazoles. US patent 4,517,199. 1985 May 14. Int C13 A61K 31/415.
62. Alcon. Iopidine® 0.5% (apraclonidine ophthalmic solution) prescribing information. In: Physicians' desk reference for ophthalmology. 24th ed. Montvale, NJ: Medical Economics Company Inc; 221-2.
63. The USP Drug Nomenclature Committee. Nomenclature policies and recommendations: I. Review and current proposals and decisions. Pharmacopeial Forum . 1991; 17:1509-11.
64. The United States Pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:128-9.
65. Alcon Laboratories Inc. Iopidine® 0.5% (apraclonidine ophthalmic solution) product monograph. Fort Worth, TX; 1993 Nov.
66. Zimmerman TJ. Timolol maleate—a new glaucoma medication? Invest Ophthalmol Visual Sci . 1977; 16:687-8. Editorial.