NDA 20258/S-030
`Page 3
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`IOPIDINE* 0.5%
`
`(apraclonidine ophthalmic solution) 0.5% As Base
`
`
`DESCRIPTION
`
`IOPIDINE* 0.5% Ophthalmic Solution contains apraclonidine hydrochloride, an alpha
`
`
`adrenergic agonist, in a sterile isotonic solution for topical application to the eye. Apraclonidine
`
`hydrochloride is a white to off-white powder and is highly soluble in water. Its chemical name is
`2-[(4-amino-2,6 dichlorophenyl) imino]imidazolidine monohydrochloride with an empirical
`
`
`
`formula of C9H11Cl3N4 and a molecular weight of 281.57. The chemical structure of
`apraclonidine hydrochloride is:
`
`Each mL of IOPIDINE 0.5% Ophthalmic Solution contains: Active: apraclonidine
`hydrochloride 5.75 mg equivalent to apraclonidine base 5 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)
`
`CLINICAL PHARMACOLOGY
`Apraclonidine hydrochloride is a relatively selective alpha-2-adrenergic agonist. When instilled
`in the eye, IOPIDINE 0.5% Ophthalmic Solution, has the action of reducing elevated, as well as
`normal, intraocular pressure (IOP), whether or not accompanied by glaucoma. Ophthalmic
`apraclonidine has minimal effect on cardiovascular parameters.
`
`Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP,
`the greater the likelihood of optic nerve damage and visual field loss. IOPIDINE 0.5%
`Ophthalmic Solution has the action of reducing IOP. The onset of action of apraclonidine can
`usually be noted within one hour, and maximum IOP reduction occurs about three hours after
`instillation. Aqueous fluorophotometry studies demonstrate that apraclonidine's predominant
`mechanism of action is reduction of aqueous flow via stimulation of the alpha-adrenergic system.
`
`Repeated dose-response and comparative studies (0.125% - 1.0% apraclonidine) demonstrate
`
`that 0.5% apraclonidine is at the top of the dose/response IOP reduction curve.
`
`The clinical utility of IOPIDINE 0.5% Ophthalmic Solution is most apparent for those glaucoma
`patients on maximally tolerated medical therapy. Patients on maximally tolerated medical
`
`therapy with uncontrolled IOP and scheduled to undergo laser trabeculoplasty or trabeculectomy
`surgery were enrolled into a double-masked, placebo-controlled, multi-center clinical trial to
`determine if IOPIDINE 0.5% Ophthalmic Solution, dosed three times daily, could delay the need
`for surgery for up to three months.
`
`Reference ID: 4227856
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`IPR Page 1/7
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`Santen/Asahi Glass Exhibit 2043
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`

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`NDA 20258/S-030
`Page 4
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`All patients enrolled into this trial had advanced glaucoma and were undergoing maximally
`tolerated medical therapy, i.e., patients were using combinations of a topical beta blocker,
`sympathomimetics, parasympathomimetics and oral carbonic anhydrase inhibitors. Patients were
`considered to be treatment failures in this study if, in the opinion of the investigators, their IOP
`was uncontrolled by the masked study medication or there was evidence of further optic nerve
`damage or visual field loss, and surgery was indicated. Of 171 patients receiving masked
`medication, 84 were treated with IOPIDINE* 0.5% Ophthalmic Solution and 87 were treated
`with placebo (apraclonidine vehicle).
`
`Apraclonidine treatment resulted in a significantly greater percentage of treatment successes
`compared to patients treated with placebo. In this placebo-controlled maximum therapy trial,
`14.3% of patients treated with IOPIDINE 0.5% Ophthalmic Solution were discontinued due to
`adverse events, primarily allergic-like reactions (12.9%).
`
`The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in
`some patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a
`variable time of onset and should be closely monitored.
`
`An unpredictable decrease of IOP control in some patients and incidence of ocular allergic
`responses and systemic side effects may limit the utility of IOPIDINE 0.5% Ophthalmic
`
`Solution. However, patients on maximally tolerated medical therapy may still benefit from the
`additional IOP reduction provided by the short-term use of IOPIDINE 0.5% Ophthalmic
`Solution.
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`Topical use of IOPIDINE 0.5% Ophthalmic Solution leads to systemic absorption. Studies of
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`IOPIDINE 0.5% Ophthalmic Solution dosed one drop three times a day in both eyes for 10 days,
`in normal volunteers, yielded mean peak and trough concentrations of 0.9 ng/mL and 0.5 ng/mL,
`respectively. The half-life of IOPIDINE 0.5% was calculated to be 8 hours.
`
`
`IOPIDINE 0.5% Ophthalmic Solution, because of its alpha adrenergic activity, is a
`vasoconstrictor. Single dose ocular blood flow studies in monkeys, using the microsphere
`technique, demonstrated a reduced blood flow for the anterior segment; however, no reduction in
`blood flow was observed in the posterior segment of the eye after a topical dose of IOPIDINE
`0.5% Ophthalmic Solution. Ocular blood flow studies have not been conducted in humans.
`
`INDICATIONS AND USAGE
`
`
`IOPIDINE 0.5% Ophthalmic Solution is indicated for short-term adjunctive therapy in patients
`on maximally tolerated medical therapy who require additional IOP reduction. Patients on
`maximally tolerated medical therapy who are treated with IOPIDINE 0.5% Ophthalmic Solution
`to delay surgery should have frequent follow-up examinations and treatment should be
`discontinued if the intraocular pressure rises significantly.
`
`The addition of IOPIDINE 0.5% Ophthalmic Solution to patients already using two aqueous
`suppressing drugs (i.e., beta-blocker plus carbonic anhydrase inhibitor) as part of their
`maximally tolerated medical therapy may not provide additional benefit. This is because
`
`Reference ID: 4227856
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`IPR Page 2/7
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`

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`NDA 20258/S-030
`Page 5
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` IOPIDINE 0.5% Ophthalmic Solution is an aqueous suppressing drug and the addition of a third
`
`aqueous suppressant may not significantly reduce IOP.
`
`
`
`The IOP lowering efficacy of IOPIDINE 0.5% Ophthalmic Solution diminishes over time in
`some patients. This loss of effect, or tachyphylaxis, appears to be an individual occurrence with a
`variable time of onset and should be closely monitored. The benefit for most patients is less than
`one month.
`
`CONTRAINDICATIONS
`
`IOPIDINE 0.5% Ophthalmic Solution is contraindicated in patients with hypersensitivity to
`apraclonidine or any other component of this medication, as well as systemic clonidine. It is also
`contraindicated in patients receiving monoamine oxidase inhibitors (MAO inhibitors).
`
`WARNINGS
`Not for injection or oral ingestion. FOR TOPICAL OPHTHALMIC USE ONLY.
`
`PRECAUTIONS
`General
`Glaucoma patients on maximally tolerated medical therapy who are treated with
`
`IOPIDINE 0.5% Ophthalmic Solution to delay surgery should have their visual fields
`monitored periodically.
`
`Although the topical use of IOPIDINE 0.5% Ophthalmic Solution has not been studied in
`renal failure patients, structurally related clonidine undergoes a significant increase in
`half-life in patients with severe renal impairment. Close monitoring of cardiovascular
`
`parameters in patients with impaired renal function is advised if they are candidates for
`topical apraclonidine therapy. Close monitoring of cardiovascular parameters in patients
`with impaired liver function is also advised as the systemic dosage form of clonidine is
`partly metabolized in the liver.
`
`While the topical administration of IOPIDINE 0.5% Ophthalmic Solution had minimal
`effect on heart rate or blood pressure in clinical studies evaluating glaucoma patients, the
`preclinical pharmacology profile of this drug suggests that caution should be observed in
`treating patients with severe, uncontrolled cardiovascular disease, including hypertension.
`The possibility of a vasovagal attack should be considered and caution should be
`exercised in patients with a history of such episodes.
`
`
`IOPIDINE 0.5% Ophthalmic Solution should be used with caution in patients with
`coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic
`renal failure, Raynaud's disease, or thromboangiitis obliterans. Caution and monitoring of
`depressed patients are advised since apraclonidine has been infrequently associated with
`depression.
`
`Apraclonidine can cause dizziness and somnolence. Patients who engage in hazardous
`activities requiring mental alertness should be warned of the potential for a decrease in
`mental alertness while using apraclonidine.
`
`Reference ID: 4227856
`
`IPR Page 3/7
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`NDA 20258/S-030
`
`Page 6
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` Topical ocular administration of two drops of 0.5, 1.0 and 1.5% apraclonidine ophthalmic
`
`
` solution to New Zealand albino rabbits three times daily for one month resulted in
`sporadic and transient instances of minimal corneal edema in the 1.5% group only; no
`histopathological changes were noted in those eyes.
`
`Use of IOPIDINE 0.5% Ophthalmic Solution can lead to an allergic-like reaction
`characterized wholly or in part by the symptoms of hyperemia, pruritus, discomfort,
`tearing, foreign body sensation, and edema of the lids and conjunctiva. If ocular allergic-
`like symptoms occur, IOPIDINE 0.5% (apraclonidine ophthalmic solution) therapy
`should be discontinued.
`
`Information for Patients
`Do not touch dropper tip to any surface as this may contaminate the contents.
`
`The preservative in IOPIDINE 0.5% Ophthalmic Solution, benzalkonium chloride, may
`be absorbed by soft contact lenses. Contact lenses should be removed during instillation
`of IOPIDINE 0.5% Ophthalmic Solution but may be reinserted 15 minutes after
`instillation.
`
`Drug Interactions
`Apraclonidine should not be used in patients receiving MAO inhibitors. (See
`
`CONTRAINDICATIONS). Although no specific drug interactions with topical glaucoma
`drugs or systemic medications were identified in clinical studies of IOPIDINE 0.5%
`Ophthalmic Solution, the possibility of an additive or potentiating effect with CNS
`depressants (alcohol, barbiturates, opiates, sedatives, anesthetics) should be considered.
`Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic
`clonidine. It is not known whether the concurrent use of these agents with apraclonidine
`can lead to a reduction in IOP lowering effect. No data on the level of circulating
`catecholamines after apraclonidine withdrawal are available. Caution, however, is
`advised in patients taking tricyclic antidepressants which can affect the metabolism and
`uptake of circulating amines.
`
`
`An additive hypotensive effect has been reported with the combination of systemic
`clonidine and neuroleptic therapy. Systemic clonidine may inhibit the production of
`catecholamines in response to insulin-induced hypoglycemia and mask the signs and
`symptoms of hypoglycemia.
`
`Since apraclonidine may reduce pulse and blood pressure, caution in using drugs such as
`beta-blockers (ophthalmic and systemic), antihypertensives, and cardiac glycosides is
`advised. Patients using cardiovascular drugs concurrently with IOPIDINE 0.5%
`Ophthalmic Solution should have pulse and blood pressures frequently monitored.
`
`Caution should be exercised with simultaneous use of clonidine and other similar
`pharmacologic agents.
`
`Reference ID: 4227856
`
`IPR Page 4/7
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`

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`NDA 20258/S-030
`Page 7
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No significant change in tumor incidence or type was observed following two years of
`oral administration of apraclonidine HCl to rats and mice at dosages of 1.0 and 0.6
`mg/kg, up to 20 and 12 times, respectively, the maximum dose recommended for human
`
`topical ocular use.
`
`Apraclonidine HCl was not mutagenic in a series of in vitro mutagenicity tests, including
`the Ames test, a mouse lymphoma forward mutation assay, a chromosome aberration
`assay in cultured Chinese hamster ovary (CHO) cells, a sister chromatid exchange assay
`in CHO cells, and a cell transformation assay. An in vivo mouse micronucleus assay
`conducted with apraclonidine HCl also provided no evidence of mutagenicity.
`Reproduction and fertility studies in rats showed no adverse effect on male or female
`
`fertility at a dose of 0.5 mg/kg (5 to 10 times the maximum recommended human dose).
`
`Pregnancy
`Apraclonidine HCl has been shown to have an embryocidal effect in rabbits when given
`in an oral dose of 3.0 mg/kg (60 times the maximum recommended human dose). Dose
`related maternal toxicity was observed in pregnant rats at 0.3 mg/kg (6 times the
`maximum recommended human dose). There are no adequate and well controlled studies
`in pregnant women. IOPIDINE 0.5% Ophthalmic Solution should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Nursing Mothers
`It is not known whether this drug is excreted in human milk. Because many drugs are
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`excreted in human milk, caution should be exercised when IOPIDINE 0.5% Ophthalmic
`Solution is administered to a nursing woman.
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`Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
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`Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and
`younger patients.
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`ADVERSE REACTIONS
`In clinical studies the overall discontinuation rate related to IOPIDINE 0.5% Ophthalmic
`Solution was 15%. The most commonly reported events leading to discontinuation included (in
`decreasing order of frequency) hyperemia, pruritus, tearing, discomfort, lid edema, dry mouth,
`and foreign body sensation.
`
`The following adverse reactions (incidences) were reported in clinical studies of IOPIDINE
`0.5% (apraclonidine ophthalmic solution) as being possibly, probably, or definitely related to
`therapy:
`
`Reference ID: 4227856
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`IPR Page 5/7
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`NDA 20258/S-030
`Page 8
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`Ocular
`
`The following adverse reactions were reported in 5 to 15% of the patients: discomfort,
`
`hyperemia, and pruritus.
`
`
`The following adverse reactions were reported in 1 to 5% of the patients: blanching, blurred
`
`vision, conjunctivitis, discharge, dry eye, foreign body sensation, lid edema, and tearing.
`
`
`The following adverse reactions were reported in less than 1% of the patients: abnormal vision,
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`blepharitis, blepharoconjunctivitis, conjunctival edema, conjunctival follicles, corneal erosion,
`
`corneal infiltrate, corneal staining, edema, irritation, keratitis, keratopathy, lid disorder, lid
`
`erythema, lid margin crusting, lid retraction, lid scales, pain, photophobia.
`
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`Nonocular
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`Dry mouth occurred in approximately 10% of the patients.
`
`
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`The following adverse reactions were reported in less than 3% of the patients: abnormal
`coordination, asthenia, arrhythmia, asthma, chest pain, constipation, contact dermatitis,
`depression, dermatitis, dizziness, dry nose, dyspnea, facial edema, headache, insomnia, malaise,
`myalgia, nausea, nervousness, paresthesia, parosmia, peripheral edema, pharyngitis, rhinitis,
`somnolence, and taste perversion.
`
`Clinical practice
`The following events have been identified during post-marketing use of IOPIDINE 0.5%
`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 0.5% Ophthalmic Solution, or a combination of these factors, include: bradycardia
`and hypersensitivity.
`
`OVERDOSAGE
`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.
`
`DOSAGE AND ADMINISTRATION
`One to two drops of IOPIDINE 0.5% Ophthalmic Solution should be instilled in the affected
`eye(s) three times daily. Since IOPIDINE 0.5% Ophthalmic Solution will be used with other
`
`Reference ID: 4227856
`
`IPR Page 6/7
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`

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`NDA 20258/S-030
`Page 9
`
`ocular glaucoma therapies, an approximate 5 minute interval between instillation of each
`medication should be practiced to prevent washout of the previous dose. NOT FOR INJECTION
`INTO THE EYE. NOT FOR ORAL INGESTION.
`
`HOW SUPPLIED
`IOPIDINE 0.5% Ophthalmic Solution as base in a sterile, isotonic, aqueous solution containing
`
`apraclonidine hydrochloride.
`
`
`Supplied in plastic ophthalmic DROP-TAINER® dispenser as follows:
`NDC 0065-0665-05
`5 mL
`NDC 0065-0665-10
`10 mL
`
`Storage: Store between 2 - 25°C (36 - 77°F).
`Protect from freezing and light.
`
`Distributed by:
`
`ALCON LABORATORIES, INC.
`
`Fort Worth, Texas 76134 USA
`
`
`Alcon®
`
`A Novartis company
`
`
`* a trademark of Novartis
`© Novartis
`
`T201X-XX
`Month Year
`
`Reference ID: 4227856
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`IPR Page 7/7
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