Iopidine 1% (apraclonidine Hydrochloride Ophthalmic Solution) 1% As Base Sterile

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

IOPIDINE 1% Ophthalmic Solution is indicated to control or prevent

post-surgical elevations in IOP that occur in patients after argon laser

trabeculoplasty, argon laser iridotomy or Nd:YAG posterior capsulotomy.

One drop of IOPIDINE* 1% Ophthalmic Solution should be instilled in the

scheduled operative eye one hour before initiating anterior segment

laser surgery and a second drop should be instilled to the same eye

immediately upon completion of the laser surgical procedure. Use

a separate container for each single‑drop dose and discard each

container after use.

IOPIDINE 1% Ophthalmic Solution as base is a sterile, isotonic, aqueous

solution containing apraclonidine hydrochloride.

Supplied as follows: 0.1 mL in plastic ophthalmic dispensers, packaged

two per pouch. These dispensers are enclosed in a foil overwrap as an

added barrier to evaporation.

0.1 mL (packaged two per pouch) NDC 82667‑200-01

Storage:Store at 2°C to 25°C (36°F‑77°F).

Protect from light.

Manufactured for:

Harrow Eye, LLC™

Nashville, TN 37205 USA

Revised: February 2023

IOPIDINE 1% Ophthalmic Solution is contraindicated for patients

receiving monoamine oxidase inhibitor therapy and for patients with

hypersensitivity to any component of this medication or to clonidine.

IOPIDINE 1% 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 ₉H ₁₁Cl ₃N ₄and a molecular weight of 281.6. The chemical structure of apraclonidine hydrochloride is:

Actives: apraclonidine hydrochloride 11.5 mg equivalent to apraclonidine base

10 mg.

Inactives:sodium chloride, sodium acetate, sodium hydroxide and/or hydrochloric acid (pH 4.4‑7.8), purified water and benzalkonium

chloride 0.01% (preservative). Osmolality is 260‑320 mOsm.

Since IOPIDINE* 1% Ophthalmic Solution is a potent depressor of IOP,

patients who develop exaggerated reductions in IOP should be closely

monitored. Although the acute administration of two drops of IOPIDINE

1% Ophthalmic Solution has minimal effect on heart rate or blood

pressure in clinical studies evaluating patients undergoing anterior

segment laser surgery, the preclinical pharmacologic profile of this drug

suggests that caution should be observed in treating patients with severe

cardiovascular disease including hypertension. IOPIDINE 1% Ophthalmic

Solution should also be used with caution in patients with severe

coronary insufficiency, recent myocardial infarction, cerebrovascular

disease, chronic renal failure, Raynaud’s disease or thromboangiitis

obliterans.

The possibility of a vasovagal attack occurring during laser surgery

should be considered and caution used in patients with history of such

episodes.

Topical ocular administration of two drops of 0.5%, 1%, and 1.5%

IOPIDINE Ophthalmic Solution to New Zealand Albino rabbits three times

daily for one month resulted in sporadic and transient instances of

minimal corneal cloudiness in the 1.5% group only. No histopathological changes were noted in those eyes. No adverse ocular effects were

observed in cynomolgus monkeys treated with two drops of 1.5%

IOPIDINE Ophthalmic Solution applied three times daily for three months.

No corneal changes were observed in 320 humans given at least one

dose of IOPIDINE 1% Ophthalmic Solution.

Interactions with other agents have not been investigated.

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 on the day of surgery.

It is not known if topically applied IOPIDINE 1% Ophthalmic Solution is

excreted in human milk. Decision should be made to discontinue nursing

temporarily for the one day on which IOPIDINE 1% Ophthalmic Solution

is used.

Safety and effectiveness in pediatric patients have not been established.

No overall differences in safety or effectiveness have been observed

between elderly and younger patients.

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 and 0.6 mg/kg/day, up to 50 and 30 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/day (25 times the

maximum recommended human dose).

The following adverse events, occurring in less than 2% of patients, were

reported in association with the use of IOPIDINE 1% Ophthalmic Solution

in laser surgery: ocular injection, upper lid elevation, irregular heart rate,

nasal decongestion, ocular inflammation, conjunctival blanching, and

mydriasis.

The following adverse events were observed in investigational studies

dosing IOPIDINE 1% Ophthalmic Solution once or twice daily for up to

28 days in non‑laser studies:

Ocular

Conjunctival blanching, upper lid elevation, mydriasis, burning, discomfort,

foreign body sensation, dryness, itching, hypotony, blurred or dimmed

vision, allergic response, conjunctival microhemorrhage.

Gastrointestinal

Abdominal pain, diarrhea, stomach discomfort, emesis

Cardiovascular

Bradycardia, vasovagal attack, palpitations, orthostatic

episode

Central Nervous System

Insomnia, dream disturbances, irritability, decreased libido.

Other

Taste abnormalities, dry mouth, nasal burning or dryness,

headache, head cold sensation, chest heaviness or burning,

clammy or sweaty palms, body heat sensation, shortness

of breath, increased pharyngeal secretion, extremity pain

or numbness, fatigue, paresthesia, pruritus not associated

with rash.

Clinical Practice

The following events have been identified during postmarketing use

of IOPIDINE 1% Ophthalmic Solution in clinical practice. Because they

are reported voluntarily from a population of unknown size, estimates

of frequency cannot be made. The events, which have been chosen for

inclusion due to either their seriousness, frequency of reporting, possible

causal connection to IOPIDINE 1% Ophthalmic Solution, or a combination

of these factors, include hypersensitivity.

Ingestion of IOPIDINE* 0.5% Ophthalmic Solution has been reported to

cause bradycardia, drowsiness, and hypothermia. Accidental or intentional

ingestion of oral clonidine has been reported to cause apnea, arrhythmias,

asthenia, bradycardia, conduction defects, diminished or absent reflexes,

dryness of the mouth, hypotension, hypothermia, hypoventilation,

irritability, lethargy, miosis, pallor, respiratory depression, sedation

or coma, seizure, somnolence, transient hypertension, and vomiting.

Treatment of an oral overdose includes supportive and symptomatic

therapy; a patent airway should be maintained. Hemodialysis is of limited

value since a maximum of 5% of circulating drug is removed.

Apraclonidine is a relatively selective, alpha adrenergic agonist and does not have significant membrane stabilizing (local anesthetic) activity. When instilled into the eye, IOPIDINE 1% (apraclonidine hydrochloride ophthalmic solution) has the action of reducing intraocular pressure (IOP). Ophthalmic apraclonidine has minimal effect on cardiovascular parameters.

Optic nerve head damage and visual field loss may result from an acute elevation in IOP that can occur after argon or Nd:YAG laser surgical procedures. Elevated IOP, whether acute or chronic in duration, is a major risk factor in the pathogenesis of visual field loss. The higher the peak or spike of IOP, the greater the likelihood of visual field loss and optic nerve damage especially in patients with previously compromised optic nerves. The onset of action with IOPIDINE 1% Ophthalmic Solution can usually be noted within one hour and the maximum IOP reduction usually occurs three to five hours after application of a single dose. The precise mechanism of the ocular hypotensive action of IOPIDINE 1% Ophthalmic Solution is not completely established at this time. Aqueous fluorophotometry studies in man suggest that its predominant action may be related to a reduction of aqueous formation. Controlled clinical studies of patients requiring argon laser trabeculoplasty, argon laser iridotomy or Nd:YAG posterior capsulotomy showed that IOPIDINE 1% Ophthalmic Solution controlled or prevented the post-surgical IOP rise typically observed in patients after undergoing those procedures. After surgery, the mean IOP was 1.2 to 4 mmHg below the corresponding pre-surgical baseline pressure before IOPIDINE Ophthalmic Solution treatment. With placebo treatment, post-surgical pressures were 2.5 to 8.4 mmHg higher than their corresponding pre-surgical baselines. Overall, only 2% of patients treated with IOPIDINE* 1% Ophthalmic Solution had severe IOP elevations (spike greater than or equal to 10 mmHg) during the first three hours after laser surgery, whereas 23% of placebo-treated patients responded with severe pressure spikes (Table 1). Of the patients that experienced a pressure spike after surgery, the peak IOP was above 30 mmHg in most patients (Table 2) and was above 50 mmHg in seven placebo-treated patients and one IOPIDINE 1% Ophthalmic Solution-treated patient.

Table 1: Incidence of IOP Spikes Greater Than or Equal to 10 mmHg

^aN = Number Spikes/Number Eyes.

Table 2: Magnitude of Post-surgical IOP in Trabeculoplasty, Iridotomy and Nd:YAG Capsulotomy Patients With Severe Pressure Spikes Greater than or Equal to 10 mmHg

Maximum Postsurgical IOP (mmHg)

Apraclonidine HCl has been shown to have an embryocidal effect in

rabbits when given in an oral dose of 3 mg/kg/day (150 times the

maximum recommended human dose). Dose related maternal toxicity

was observed in pregnant rats at 0.3 mg/kg/day (15 times the maximum

recommended human dose). There are no adequate and well controlled

studies in pregnant women. IOPIDINE* 1% Ophthalmic Solution should be

used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

NDC 82667-200-01



IOPIDINE®

(apraclonide hydrochloride ophthalmic solution)

1% as base

Sterile

CONTENTS: 12 pouches containing 2 units, 0.1mL each

Store at 2°-25°C (36°-77°F). Protect from light.

Rx Only

HARROW®

Manufactured for:

Harrow Eye, LLC,

Nashville, TN 37205 USA

Made in France

IOPIDINE 1% Ophthalmic Solution is indicated to control or prevent

post-surgical elevations in IOP that occur in patients after argon laser

trabeculoplasty, argon laser iridotomy or Nd:YAG posterior capsulotomy.

One drop of IOPIDINE* 1% Ophthalmic Solution should be instilled in the

scheduled operative eye one hour before initiating anterior segment

laser surgery and a second drop should be instilled to the same eye

immediately upon completion of the laser surgical procedure. Use

a separate container for each single‑drop dose and discard each

container after use.

IOPIDINE 1% Ophthalmic Solution as base is a sterile, isotonic, aqueous

solution containing apraclonidine hydrochloride.

Supplied as follows: 0.1 mL in plastic ophthalmic dispensers, packaged

two per pouch. These dispensers are enclosed in a foil overwrap as an

added barrier to evaporation.

0.1 mL (packaged two per pouch) NDC 82667‑200-01

Storage:Store at 2°C to 25°C (36°F‑77°F).

Protect from light.

Manufactured for:

Harrow Eye, LLC™

Nashville, TN 37205 USA

Revised: February 2023

IOPIDINE 1% Ophthalmic Solution is contraindicated for patients

receiving monoamine oxidase inhibitor therapy and for patients with

hypersensitivity to any component of this medication or to clonidine.

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

Since IOPIDINE* 1% Ophthalmic Solution is a potent depressor of IOP,

patients who develop exaggerated reductions in IOP should be closely

monitored. Although the acute administration of two drops of IOPIDINE

1% Ophthalmic Solution has minimal effect on heart rate or blood

pressure in clinical studies evaluating patients undergoing anterior

segment laser surgery, the preclinical pharmacologic profile of this drug

suggests that caution should be observed in treating patients with severe

cardiovascular disease including hypertension. IOPIDINE 1% Ophthalmic

Solution should also be used with caution in patients with severe

coronary insufficiency, recent myocardial infarction, cerebrovascular

disease, chronic renal failure, Raynaud’s disease or thromboangiitis

obliterans.

The possibility of a vasovagal attack occurring during laser surgery

should be considered and caution used in patients with history of such

episodes.

Topical ocular administration of two drops of 0.5%, 1%, and 1.5%

IOPIDINE Ophthalmic Solution to New Zealand Albino rabbits three times

daily for one month resulted in sporadic and transient instances of

minimal corneal cloudiness in the 1.5% group only. No histopathological changes were noted in those eyes. No adverse ocular effects were

observed in cynomolgus monkeys treated with two drops of 1.5%

IOPIDINE Ophthalmic Solution applied three times daily for three months.

No corneal changes were observed in 320 humans given at least one

dose of IOPIDINE 1% Ophthalmic Solution.

Interactions with other agents have not been investigated.

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 on the day of surgery.

It is not known if topically applied IOPIDINE 1% Ophthalmic Solution is

excreted in human milk. Decision should be made to discontinue nursing

temporarily for the one day on which IOPIDINE 1% Ophthalmic Solution

is used.

Safety and effectiveness in pediatric patients have not been established.

No overall differences in safety or effectiveness have been observed

between elderly and younger patients.

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 and 0.6 mg/kg/day, up to 50 and 30 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/day (25 times the

maximum recommended human dose).

The following adverse events, occurring in less than 2% of patients, were

reported in association with the use of IOPIDINE 1% Ophthalmic Solution

in laser surgery: ocular injection, upper lid elevation, irregular heart rate,

nasal decongestion, ocular inflammation, conjunctival blanching, and

mydriasis.

The following adverse events were observed in investigational studies

dosing IOPIDINE 1% Ophthalmic Solution once or twice daily for up to

28 days in non‑laser studies:

Ocular

Conjunctival blanching, upper lid elevation, mydriasis, burning, discomfort,

foreign body sensation, dryness, itching, hypotony, blurred or dimmed

vision, allergic response, conjunctival microhemorrhage.

Gastrointestinal

Abdominal pain, diarrhea, stomach discomfort, emesis

Cardiovascular

Bradycardia, vasovagal attack, palpitations, orthostatic

episode

Central Nervous System

Insomnia, dream disturbances, irritability, decreased libido.

Other

Taste abnormalities, dry mouth, nasal burning or dryness,

headache, head cold sensation, chest heaviness or burning,

clammy or sweaty palms, body heat sensation, shortness

of breath, increased pharyngeal secretion, extremity pain

or numbness, fatigue, paresthesia, pruritus not associated

with rash.

Clinical Practice

The following events have been identified during postmarketing use

of IOPIDINE 1% Ophthalmic Solution in clinical practice. Because they

are reported voluntarily from a population of unknown size, estimates

of frequency cannot be made. The events, which have been chosen for

inclusion due to either their seriousness, frequency of reporting, possible

causal connection to IOPIDINE 1% Ophthalmic Solution, or a combination

of these factors, include hypersensitivity.

Ingestion of IOPIDINE* 0.5% Ophthalmic Solution has been reported to

cause bradycardia, drowsiness, and hypothermia. Accidental or intentional

ingestion of oral clonidine has been reported to cause apnea, arrhythmias,

asthenia, bradycardia, conduction defects, diminished or absent reflexes,

dryness of the mouth, hypotension, hypothermia, hypoventilation,

irritability, lethargy, miosis, pallor, respiratory depression, sedation

or coma, seizure, somnolence, transient hypertension, and vomiting.

Treatment of an oral overdose includes supportive and symptomatic

therapy; a patent airway should be maintained. Hemodialysis is of limited

value since a maximum of 5% of circulating drug is removed.

IOPIDINE 1% 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 ₉H ₁₁Cl ₃N ₄and a molecular weight of 281.6. The chemical structure of apraclonidine hydrochloride is:

Actives: apraclonidine hydrochloride 11.5 mg equivalent to apraclonidine base

10 mg.

Inactives:sodium chloride, sodium acetate, sodium hydroxide and/or hydrochloric acid (pH 4.4‑7.8), purified water and benzalkonium

chloride 0.01% (preservative). Osmolality is 260‑320 mOsm.

Apraclonidine is a relatively selective, alpha adrenergic agonist and does not have significant membrane stabilizing (local anesthetic) activity. When instilled into the eye, IOPIDINE 1% (apraclonidine hydrochloride ophthalmic solution) has the action of reducing intraocular pressure (IOP). Ophthalmic apraclonidine has minimal effect on cardiovascular parameters.

Optic nerve head damage and visual field loss may result from an acute elevation in IOP that can occur after argon or Nd:YAG laser surgical procedures. Elevated IOP, whether acute or chronic in duration, is a major risk factor in the pathogenesis of visual field loss. The higher the peak or spike of IOP, the greater the likelihood of visual field loss and optic nerve damage especially in patients with previously compromised optic nerves. The onset of action with IOPIDINE 1% Ophthalmic Solution can usually be noted within one hour and the maximum IOP reduction usually occurs three to five hours after application of a single dose. The precise mechanism of the ocular hypotensive action of IOPIDINE 1% Ophthalmic Solution is not completely established at this time. Aqueous fluorophotometry studies in man suggest that its predominant action may be related to a reduction of aqueous formation. Controlled clinical studies of patients requiring argon laser trabeculoplasty, argon laser iridotomy or Nd:YAG posterior capsulotomy showed that IOPIDINE 1% Ophthalmic Solution controlled or prevented the post-surgical IOP rise typically observed in patients after undergoing those procedures. After surgery, the mean IOP was 1.2 to 4 mmHg below the corresponding pre-surgical baseline pressure before IOPIDINE Ophthalmic Solution treatment. With placebo treatment, post-surgical pressures were 2.5 to 8.4 mmHg higher than their corresponding pre-surgical baselines. Overall, only 2% of patients treated with IOPIDINE* 1% Ophthalmic Solution had severe IOP elevations (spike greater than or equal to 10 mmHg) during the first three hours after laser surgery, whereas 23% of placebo-treated patients responded with severe pressure spikes (Table 1). Of the patients that experienced a pressure spike after surgery, the peak IOP was above 30 mmHg in most patients (Table 2) and was above 50 mmHg in seven placebo-treated patients and one IOPIDINE 1% Ophthalmic Solution-treated patient.

Table 1: Incidence of IOP Spikes Greater Than or Equal to 10 mmHg

^aN = Number Spikes/Number Eyes.

Table 2: Magnitude of Post-surgical IOP in Trabeculoplasty, Iridotomy and Nd:YAG Capsulotomy Patients With Severe Pressure Spikes Greater than or Equal to 10 mmHg

Maximum Postsurgical IOP (mmHg)

Apraclonidine HCl has been shown to have an embryocidal effect in

rabbits when given in an oral dose of 3 mg/kg/day (150 times the

maximum recommended human dose). Dose related maternal toxicity

was observed in pregnant rats at 0.3 mg/kg/day (15 times the maximum

recommended human dose). There are no adequate and well controlled

studies in pregnant women. IOPIDINE* 1% Ophthalmic Solution should be

used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

NDC 82667-200-01



IOPIDINE®

(apraclonide hydrochloride ophthalmic solution)

1% as base

Sterile

CONTENTS: 12 pouches containing 2 units, 0.1mL each

Store at 2°-25°C (36°-77°F). Protect from light.

Rx Only

HARROW®

Manufactured for:

Harrow Eye, LLC,

Nashville, TN 37205 USA

Made in France