Professional Drug Information > P-aminoclonidine

Apraclonidine (Ophthalmic)

VA CLASSIFICATION
Primary: OP114

Commonly used brand name(s): Iopidine.

Other commonly used names are
aplonidine ^{02} and p-aminoclonidine . ^{05}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiglaucoma agent (ophthalmic)—

antihypertensive, ocular—^{04}

Indications

Accepted

Glaucoma, open angle (treatment)—Apraclonidine 0.5% is indicated for short-term adjunctive therapy in patients who are on maximally tolerated doses of other medications intended to reduce intraocular pressure (IOP) and who need additional IOP reduction. ^{{15} {40}} Patients who already receive two aqueous suppressing medications (e.g., a beta-adrenergic blocking agent and a carbonic anhydrase inhibitor) may not derive additional IOP reduction from the addition of apraclonidine to their treatment regimen, since apraclonidine is also an aqueous-suppressing medication. ^{{15} {18} {26} {40}}

Hypertension, ocular (prophylaxis and treatment)—Apraclonidine 1% is indicated to control or prevent postsurgical elevations in intraocular pressure that occur in patients after argon laser trabeculoplasty, argon laser iridotomy, or Nd:YAG ^{14} laser ^{11} posterior capsulotomy. ^{{01} {05} {08} {09} {14} {16} {19} {20} {22} {23} {24} {25} {27} {28} {30} {32} {33} {35} {40}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    281.57 ^{{07} {14} {15}}

pKa—
    9.22 ^{05}


Other characteristics
    The pH of apraclonidine hydrochloride ophthalmic solution is 4.4 to 7.8 ^{05}

Mechanism of action/Effect:

Apraclonidine is a relatively selective alpha ₂ ^{{04} {05} {10}} adrenergic agonist. ^{{01} {14} {15} {26} {30}} When instilled into the eye, apraclonidine ophthalmic solution reduces elevated, as well as normal, ^{15} intraocular pressure. ^{{01} {10} {14} {15}} Aqueous fluorophotometry studies demonstrate that the predominant mechanism of action of ophthalmic apraclonidine is the reduction of aqueous humor flow via stimulation of the alpha-adrenergic system. ^{15}


Other actions/effects:

Apraclonidine does not have significant membrane stabilizing (local anesthetic) activity. ^{{01} {14}} In addition, ophthalmic apraclonidine has minimal effect on cardiovascular parameters. ^{{01} {14} {15} {29} {31}}

Half-life:

For 0.5% apraclonidine—8 hours. ^{15}

Onset of action:

Usually within one hour. ^{{01} {14} {15}}

Peak serum concentration:

For 0.5% apraclonidine—0.9 nanograms per mL. ^{15}

Time to peak effect:

Usually three to five hours after application of a single dose. ^{{01} {14} {15} {34}}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to clonidine may be sensitive to apraclonidine also. ^{{01} {06} {08} {14} {15}}

Carcinogenicity

Rats and mice administered oral apraclonidine for 2 years in doses of 1 and 0.6 mg per kg of body weight (mg/kg), respectively, did not have any significant change in tumor incidence or type. ^{15}

Mutagenicity

Apraclonidine was not shown to be mutagenic in an in vivo mouse micronucleus assay and 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. ^{15}

Pregnancy/Reproduction
Fertility—
Studies on reproduction and fertility in male and female rats given 0.5 mg/kg of apraclonidine have not shown adverse effects on fertility. ^{15}

Pregnancy—
Adequate and well-controlled studies have not been done in humans. ^{{14} {15}}

Apraclonidine has been shown to have an embryocidal effect on rabbits that were given 3 mg/kg apraclonidine orally. Dose-related maternal toxicity was observed in pregnant rats given 0.3 mg/kg apraclonidine. ^{15}

FDA Pregnancy Category C. ^{{01} {05} {08} {14} {15}}

Breast-feeding

It is not known whether ophthalmic apraclonidine is distributed into breast milk. ^{{01} {05} {08} {14} {15}} However, problems in humans have not been documented. It is recommended that patients do not breast-feed on the day on which 1% apraclonidine is administered. ^{{04} {08} {14}}

Pediatrics

Appropriate studies on the relationship of age to the effects of apraclonidine have not been performed in the pediatric population. Safety and efficacy have not been established. ^{{08} {14} {15}}


Geriatrics


No information is available on the relationship of age to the effects of apraclonidine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (some clinicians believe that apraclonidine should not be used during or within 14 days following administration of MAO inhibitors, because the antihypertensive effects of either apraclonidine or the MAO inhibitor may be potentiated by concurrent use; however, this is controversial ^{{08} {11} {14} {15} {37}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease, severe, including hypertension or^{01}{14}{15}
Cerebrovascular disease or^{15}
Coronary insufficiency or^{15}
Myocardial infarction, recent or^{15}
Raynaud's disease or^{15}
Thromboangiitis obliterans^{15}    (in clinical studies, the total usual adult dose of 2 drops of 1% ^{14} and short-term three-times-a-day use of 0.5% ^{15} ophthalmic apraclonidine had minimal effect on heart rate and blood pressure. ^{{01} {03} {14} {15} {29} {31}} However, since there is a possibility of systemic absorption and because apraclonidine is a potent medication, caution should be used when administering 0.5 or 1% apraclonidine to patients who have severe cardiovascular disease, including hypertension, and when administering 0.5% apraclonidine to patients with other cardiovascular diseases ^{{14} {15}})


Depression    (use of apraclonidine 0.5% has been infrequently associated with depression; caution is recommended when apraclonidine is used in patients with depression ^{15})


Exaggerated response to medications that reduce intraocular pressure^{01}{14}    (patients who exhibit an exaggerated response to medications that reduce intraocular pressure should be closely monitored during treatment with apraclonidine, since apraclonidine is a potent depressor of intraocular pressure ^{{01} {04} {14}})


Hepatic function impairment    (since a structurally related medication, clonidine, is partly metabolized in the liver, monitoring of cardiovascular parameters in patients with liver function impairment who are using apraclonidine 0.5% is recommended ^{{15} {37}})


Renal function impairment    (since a structurally related medication, clonidine, undergoes a significant increase in half-life in patients with severe renal impairment, monitoring of cardiovascular parameters in patients with renal function impairment who are using apraclonidine 0.5% is recommended ^{{15} {37}})


Sensitivity to apraclonidine
Vasovagal attack, history of^{01}{14}    (the possibility of a vasovagal attack occurring during laser surgery should be considered; caution should be used when administering 1% apraclonidine to patients with a history of this medical problem ^{{01} {04} {05} {14}})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Ophthalmology examinations    (patients using 0.5% apraclonidine should have frequent followup examinations to check intraocular pressure, and their visual fields should be monitored periodically ^{15})






Side/Adverse Effects

Note: Ophthalmic apraclonidine 0.5% used three times a day is systemically absorbed; the 2 drops of ophthalmic apraclonidine 1% used during laser surgery may also be systemically absorbed, but it may not be as likely to cause systemic side/adverse effects as is the 0.5% dosage. ^{{14} {15} {38}}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
For 0.5% ophthalmic apraclonidine
    
Allergic reaction^{15}{18} (redness of eye; itching of eye; tearing of eye)


Incidence less frequent or rare
For 0.5% ophthalmic apraclonidine
    
Abnormal coordination^{15} (clumsiness or unsteadiness)
    
arrhythmia^{15} (irregular heartbeat)
    
asthma^{15} (wheezing or troubled breathing)
    
blepharitis^{15}
blepharoconjunctivitis^{15}
conjunctivitis^{15} (redness of eye, eyelid, or inner lining of eyelid)
    
blurred vision or change in vision^{15}
    
chest pain^{15}
    
contact dermatitis^{15} (rash around eyes)
    
corneal erosion^{15}
corneal infiltrate^{15}
foreign body sensation^{15}
keratitis^{15}
keratopathy^{15} (eye redness, irritation, or pain)
    
^{15}depression^{15}
    
dizziness^{15}
    
dyspnea^{15} (troubled breathing)
    
edema of eye, eyelid, or conjunctiva^{15} (swelling of eye, eyelid, or inner lining of eyelid)
    
eye discharge^{15}
    
facial edema^{15} (swelling of face)
    
lid retraction^{15}{38} (raising of upper eyelid)
    
paresthesia^{15} (numbness or tingling in fingers or toes)
    
peripheral edema^{15} (swelling of hands or feet)

For 1% ophthalmic apraclonidine
    
Allergic reaction^{05}{08}{14} (redness of eye or inner lining of eyelid, swelling of eyelid, or watering of eye)
    
arrhythmia^{08}{14} (irregular heartbeat)
    
ocular inflammation or injection^{08}{14} (redness of eye)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
For 0.5% ophthalmic apraclonidine
    
Dryness of mouth^{15}{36}
    
eye discomfort^{15}

For 1% ophthalmic apraclonidine ^{{01} {03} {04}}
    
Conjunctival blanching^{{01}{03}{04}{05}{08}{14}{21}{34}} (paleness of eye or inner lining of eyelid)
    
lid retraction^{{01}{03}{04}{05}{08}{14}{21}{34}{38}} (raising of upper eyelid)
    
mydriasis^{{01}{03}{04}{05}{08}{14}{17}{21}} (increase in size of pupil of eye)


Incidence less frequent or rare
For 0.5% ophthalmic apraclonidine
    
Asthenia^{15} (tiredness or weakness)
    
conjunctival blanching^{15} (paleness of eye or inner lining of eyelid)
    
constipation^{15}
    
corneal staining^{15} (discoloration of white part of eye)
    
crusting or scales on eyelid or corner of eye^{15}
    
dry nose^{15}{36} or eyes^{15}
    
headache^{15}
    
insomnia^{15} (trouble in sleeping)
    
malaise^{15} (general feeling of discomfort or illness)
    
myalgia^{15} (muscle aches)
    
nausea^{15}
    
nervousness^{15}
    
parosmia or taste perversion^{15} (change in taste or smell)
    
pharyngitis^{15} (sore throat)
    
photophobia^{15} (increased sensitivity of eyes to light)
    
rhinitis^{15} (runny nose)
    
somnolence^{15} (drowsiness or sleepiness)

For 1% ophthalmic apraclonidine
    
Nasal decongestion^{14} (runny nose)






Overdose
No information is available regarding overdosage of apraclonidine in humans. ^{{01} {08} {14} {15}}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Apraclonidine (Ophthalmic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to apraclonidine or clonidine

Pregnancy—Fetal death occurred after the administration of large oral doses of apraclonidine in rabbit studies





Breast-feeding—It may be necessary to stop breast-feeding during the day of surgery
Other medical problems, especially severe cardiovascular disease, including hypertension

Proper use of this medication
Waiting at least 10 minutes between instillation of two different ophthalmic solutions ^{{38} {39}}

Proper administration technique; using a second drop if necessary; not touching applicator tip to any surface; keeping container tightly closed

» Importance of not using more medication than the amount prescribed

» Regular visits to physician to check eye pressure during therapy

» Proper dosing
Missed dose: Using as soon as possible; not using if almost time for next dose; using next dose at regularly scheduled time; not doubling doses

» Proper storage

Precautions while using this medication
» Medication may cause dizziness or drowsiness; using caution when driving, using machines, or doing anything else requiring alertness

Possible photophobia; wearing sunglasses or avoiding bright light


Side/adverse effects

Signs of potential side effects, especially
For 0.5% ophthalmic apraclonidineAllergic reaction, abnormal coordination, arrhythmia, asthma, blepharitis, blepharoconjunctivitis, conjunctivitis, blurred vision or change in vision, chest pain, contact dermatitis, corneal erosion, corneal infiltrate, foreign body sensation, keratitis, keratopathy, depression, dizziness, dyspnea, edema of eye, eyelid, or conjunctiva, eye discharge, facial edema, lid retraction, paresthesia, or peripheral edema

For 1% ophthalmic apraclonidineAllergic reaction, arrhythmia, or ocular inflammation or injection


General Dosing Information
The intraocular pressure (IOP) lowering efficacy of 0.5% ophthalmic apraclonidine diminishes over time and the benefit for most patients is less than one month. ^{15}

When instilling two different ophthalmic solutions, patient should wait at least 10 minutes between instillations to avoid a ``wash-out'' effect. ^{{15} {38} {39}}

If hypersensitivity develops, therapy with ophthalmic apraclonidine should be discontinued. ^{15}


Ophthalmic Dosage Forms

APRACLONIDINE HYDROCHLORIDE OPHTHALMIC SOLUTION

Usual adult and adolescent dose
Open angle glaucoma
Topical, to the conjunctiva, 1 drop of 0.5% solution in each eye two or ^{40} three times a day.
^{15}{40}
Ocular hypertension
Topical, to the conjunctiva, 1 drop of 1% solution in the affected eye one hour before initiating anterior segment laser surgery and 1 drop in the same eye immediately upon completion of the laser surgical procedure. ^{{01} {06} {08} {14} {40}}


Usual pediatric dose
Safety and efficacy have not been established. ^{{08} {14} {15}}

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


0.5% (base) (Rx) [Iopidine^{15} (benzalkonium chloride 0.01%)]


1% (base) (Rx) [Iopidine^{{01}{08}{12}{14}} (benzalkonium chloride 0.01%)]

Canada—


0.5% (base) (Rx) [Iopidine^{40} (benzalkonium chloride 0.01%)]


1% (base) (Rx) [Iopidine^{13} (benzalkonium chloride 0.01%)]

Note: Each mL of the 0.5% solution contains 5.75 mg of apraclonidine HCl equivalent to 5 mg of apraclonidine base. ^{15}
Each mL of the 1% solution contains 11.5 mg of apraclonidine hydrochloride equivalent to 10 mg of apraclonidine base. ^{{01} {14}}


Packaging and storage:
For the 0.5% solution—Store between 2 and 27 °C (36 and 80 °F), ^{15} unless otherwise specified by manufacturer. Protect from freezing and light. ^{15}

For the 1% solution—Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), ^{{01} {14}} unless otherwise specified by manufacturer. Protect from freezing and light. ^{{01} {14}}

Auxiliary labeling:
   • For the eye.
   • Protect from light. ^{{14} {15}}
   • Do not freeze. ^{{14} {15}}

Revised: 07/03/1995

References

1. Iopidine 1% package insert (Alcon—US), Rev 1/88, Rec 6/88.
   

2. Products pending. PharmIndex October 1988; 30(10): 16.
   

3. Robin AL. Short-term effects of unilateral 1% apraclonidine therapy. Arch Ophthalmol 1988 Jul; 106(7): 912-5.
   

4. Panel comments, 12/88.
   

5. McEvoy GK, editor. AHFS drug information 88. Bethesda, MD: American Society of Hospital Pharmacists, 1988: (Suppl B).
   

6. Iopidine 1% package insert (Alcon—US), Rev 5/88, Rec 1/89.
   

7. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1993.
   

8. Iopidine 1% package insert (Alcon—US), Rev 12/89, Rec 7/90.
   

9. Pollack IP, et al. Prevention of the rise in intraocular pressure following neodymium-YAG posterior capsulotomy using topical 1% apraclonidine. Arch Ophthalmol 1988 Jun; 106(6): 754-7.
   

10. Abrams DA, et al. A limited comparison of apraclonidine's dose response in subjects with normal or increased intraocular pressure. Am J Ophthalmol 1989 Sep; 108: 230-7.
    

11. Panel comments, 1/91.
    

12. Iopidine 1% (Alcon). In: PDR Physicians' desk reference for ophthalmology. 19th ed. 1991. Montvale, NJ: Medical Economics Data, 1991: 230.
    

13. Iopidine 1% (Alcon). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 598.
    

14. Iopidine 1% (Alcon). In: PDR Physicians' desk reference for ophthalmology. 22nd ed. 1994. Montvale, NJ: Medical Economics Data, 1994: 216.
    

15. Iopidine 0.5% package insert (Alcon—US), Rev 7/93, Rec 11/93.
    

16. Cullom RD Jr, Schwartz LW. The effect of apraclonidine on the intraocular pressure of glaucoma patients following Nd: YAG laser posterior capsulotomy. Ophthalmic Surg 1993 Sep; 24(9): 623-6.
    

17. Hong C, Song KY. Effect of apraclonidine hydrochloride on the attack of Posner-Schlossman syndrome. Korean J Ophthalmol 1993 Jun; 7(1): 28-33.
    

18. Nagasubramanian S, Hitchings RA, Demailly P, et al. Comparison of apraclonidine and timolol in chronic open-angle glaucoma. A three-month study. Ophthalmology 1993 Sep; 100(9): 1318-23.
    

19. Araie M, Ishi K. Effects of apraclonidine on intraocular pressure and blood-aqueous barrier permeability after phacoemulsification and intraocular lens implantation. Am J Ophthalmol 1993 Jul 15; 116(1): 67-71.
    

20. Robin AL. Effect of topical apraclonidine on the frequency of intraocular pressure elevations after combined extracapsular cataract extraction and trabeculectomy. Ophthalmology 1993 May; 100(5): 628-33.
    

21. Yuksel N, Guler C, Caglar Y, Elibol O. Apraclonidine and clonidine: a comparison of efficacy and side effects in normal and ocular hypertensive volunteers. Int Ophthalmol 1992 Sep; 16(4-5): 337-42.
    

22. Holmwood PC, Chase RD, Krupin T, et al. Apraclonidine and argon laser trabeculoplasty. Comment in: Am J Ophthalmol 1992 Dec 15; 114(6): 778-9. Am J Ophthalmol 1992 Jul 15; 114(1): 19-22.
    

23. Silverstone DE, Brint SF, Olander KW, et al. Prophylactic use of apraclonidine for intraocular pressure increase after Nd: YAG capsulotomies [comment]. Am J Ophthalmol 1992 Sep 15; 114(3): 377-9. Comment on: Am J Ophthalmol 1992 Apr 15; 113(4): 401-5.
    

24. Allf BE, Shields MB. Early intraocular pressure response to laser trabeculoplasty 180 degrees without apraclonidine versus 360 degrees with apraclonidine. Ophthalmic Surg 1991 Sep; 22(9): 539-42.
    

25. Hong C, Song KY, Park WH, Sohn YH. Effect of apraclonidine hydrochloride on acute intraocular pressure rise after argon laser iridotomy. Korean J Ophthalmol 1991 Jun; 5(1): 37-41.
    

26. Koskela T, Brubaker RF. Apraclonidine and timolol. Combined effects in previously untreated normal subjects. Arch Ophthalmol 1991 Jun; 109(6): 804-6.
    

27. Robin AL. Argon laser trabeculoplasty medical therapy to prevent the intraocular pressure rise associated with argon laser trabeculoplasty. Ophthalmic Surg 1991 Jan; 22(1): 31-7.
    

28. Nesher R, Kolker AE. Failure of apraclonidine to prevent delayed IOP elevation after Nd: YAG laser posterior capsulotomy. Trans Am Ophthalmol Soc 1990; 88: 229-32; discussion 233-6.
    

29. Robin AL, Coleman AL. Apraclonidine hydrochloride: an evaluation of plasma concentrations, and a comparison of its intraocular pressure lowering and cardiovascular effects to timolol maleate. Trans Am Ophthalmol Soc 1990; 88: 149-59; discussion 159-62.
    

30. Fernandez-Bahamonde JL, Alcaraz-Michelli V. The combined use of apraclonidine and pilocarpine during laser iridotomy in a Hispanic population. Ann Ophthalmol 1990 Dec; 22(12): 446-9.
    

31. Coleman AL, Robin AL, Pollack IP, et al. Cardiovascular and intraocular pressure effects and plasma concentrations of apraclonidine. Arch Ophthalmol 1990 Sep; 108(9): 1264-7.
    

32. Robin AL. The role of apraclonidine hydrochloride in laser therapy for glaucoma. Trans Am Ophthalmol Soc 1990; 87: 729-61.
    

33. Sridharrao B, Badrinath SS. Efficacy and safety of apraclonidine in patients undergoing anterior segment laser surgery. Br J Ophthalmol 1989 Nov; 73(11): 884-7.
    

34. Serdahl CL, Galustian J, Lewis RA. The effects of apraclonidine on conjunctival oxygen tension. Arch Ophthalmol 1989 Dec; 107(12): 1777-9.
    

35. Pollack IP, Brown RH, Crandall AS, et al. Effectiveness of apraclonidine in preventing the rise in intraocular pressure after neodymium: YAG posterior capsulotomy. Trans Am Ophthalmol Soc 1988; 86: 461-72.
    

36. Jampel HD, Robin AL, Quigley HA, Pollack IP. Apraclonidine. A one-week dose-response study. Arch Ophthalmol 1988 Aug; 106(8): 1069-73.
    

37. Reviewers' consensus on monograph revision of 2/23/94.
    

38. Panel comments, 4/6/94.
    

39. Timoptic-XE package insert (Merck—US), Rev 11/93, Rec 3/94.
    

40. Iopidine 0.5 and 1% product monograph (Alcon—Canada), Rev 2/15/94, Rec 6/2/95.
    

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