SENJU EXHIBIT 2093
`LUPIN v SENJU
`IPR2015-01105
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`PAGE 1 OF 7
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`NDA 21-262
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`Page 3
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`E Allergan, Inc.
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`ALr11AcAN' P
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`(brimonidine tartrate ophthalmic solution) 0.15%
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`Sterile
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`DESCRIPTION
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`ALPHAGAN° P (brimonidine tartrate ophthalmic solution) 0.15% is a relatively selective
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`alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 5-
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`bromo-6-(2—imidazolidinylideneamino) quinoxaline L-tartrate. It is an off-white to pale yellow
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`powder. It has a molecular weight of 442.24 as the tartmte salt, and is both soluble in water (1.5
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`mymL) and in the product vehicle (3.0 mg/mL) at pH 7.2. The structural formula is:
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`I
`HN
`NH
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`Y Br
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`E .N
`D
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`N
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`N
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`COOH
`I
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`H—(|2-OH
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`H0-('2—}-I
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`COOH
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`Formula: CnH1oBl’N5'C4H505
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`CAS Number: 59803-98-4
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`In solution, ALPHAGAN° P (brimonidine tartrate ophthalmic solution) 0.15% has a clear,
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`greenish-yellow color. It has an osmolality of 250-350 mOsmol/kg and a pH of 6.6-7.4.
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`Each mL of ALPHAGAN° P contains:
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`Active ingredient: brimonidine tartrate 0.15% (1.5 mg/mL)
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`Preservative: Pun'te° 0.005% (0.05mg.mL)
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`Inactives: sodium carboxymethylcellulose; sodium borate; boric acid; sodium-chloride;
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`potassium chloride; calcium chloride; magnesium chloride; purified water; with hydrochloric
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`acid and/or sodium hydroxide to adjust pH.
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`PAGE 2 OF 7
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`PAGE 2 OF 7
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`NDA 21-262
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`Page 4
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`CLINICAL PHARMACOLOGY
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`Mechanism of action:
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`ALPI-lAGAN° P is an alpha adrenergic receptor agonist. It has a peak ocular hypotensive efl'ect
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`occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest
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`that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production
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`and increasing uveoscleral outflow.
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`Pharmacokinetlcs:
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`Afier ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked
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`within 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours. In
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`humans, systemic metabolism of brimonidine is extensive. It is metabolized primarily by the
`liver. Urinary excretion is the major route of elimination of the drug and its metabolites.
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`Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours,
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`with 74% found in the urine.
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`Clinical Evaluations:
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`Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of
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`IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate
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`has the action of lowering intraocular pressure with minimal effect on cardiovascular and
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`pulmonary parameters.
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`Two clinical studies were conducted to evaluate the safety, efficacy, and acceptability of
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`ALPHAGAN° P (brirnonidine mm: ophthalmic solution) 0.15% compared with
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`ALPHAGAN' administered three-times-daily in patients with open-angle glaucoma or ocular
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`hypertension. Those results indicated that ALPHAGAN' P (brimonidine tartrate ophthalmic
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`solution) 0.15% is comparable in IOP lowering effect to ALPHAGAN® (brimonidine tartrate
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`ophthalmic solution) 0.2%, and effectively lowers IOP in patients with open-angle glaucoma or
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`ocular hypertension by approximately 2-Smml-lg.
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`_/‘x
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`PAGE 3 OF 7
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`PAGE 3 OF 7
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`NDA 21-262
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`Page 5
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`INDICATIONS AND USAGE
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`ALP]-lAGAN° P is indicated for the lowering of intraocular pressure in patients with open-angle
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`glaucoma or ocular hypertension.
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`CONTRAINDICATIONS
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`ALPHAGAN’ P is contraindicated in patients with hypersensitivity to brimonidine tartrate or
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`any component of this medication. It is also contraindicated in patients receiving monoamine
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`oxidase (MAO) inhibitor therapy.
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`PRECAUTIONS
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`General:
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`Although ALPHAGAN’ P had minimal effect on the blood pressure of patients in clinical
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`studies, caution should be exercised in treating patients with severe cardiovascular disease.
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`ALPHAGAN° P has not been studied in patients with hepatic or renal impairment; caution
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`should be used in treating such patients.
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`ALPHAGAN° P should be used with caution in patients with depression, cerebral or coronary
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`insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
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`Patients prescribed IOP-lowering medication should be routinely monitored for IOP.
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`Information for Patients:
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`As with other drugs in this class, ALPHAG.-SN‘ P may cause fatigue and/or drowsiness in some
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`patients. Patients who engage in hazardous activities should be cautioned of the potential for a
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`decrease in mental alertness.
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`PAGE 4 OF 7
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`PAGE 4 OF 7
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`NDA 21-262
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`Page 6
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`Drug Interactions:
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`Although specific drug interaction studies have not been conducted with ALPHAGAN° P, the
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`possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates,
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`opiates, sedatives, or anesthetics) should be considered. Alpha-agonists, as a class, may reduce
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`pulse and blood pressure. Caution in using concomitant drugs such as beta-blockers (ophthalmic
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`and systemic), anti-hypertensives and/or cardiac glycosides is advised.
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`Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic
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`clonidine. It is not known whether the concurrent use of these agents with ALPHAGAN’ P in
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`humans can lead to resulting interference with the IOP lowering effect. No data on the level of
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`circulating catecholamines afier ALPHAGAN° P administration are available. Caution,
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`however, is advised in patients taking tricyclic antidepressants which can affect the metabolism
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`and uptake of circulating amines.
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`Carcinogenesis, Mutagenesis, and Impairment of Fertility:
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`No compound-related carcinogenic effects were observed in either mice or rats following a 21-
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`month and 24-month study, respectively. In these studies, dietary administration of brimonidine
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`tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved 86 and 55 times,
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`respectively, the plasma drug concentration estimated in humans treated with one drop
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`AL1>uAcAN' P into both eyes 3 times per day.
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`Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies
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`including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a
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`host-mediated assay and cytogenic studies in mice, and dominant lethal assay.
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`Pregnancy: Teratogenic effects: Pregnancy Category B.
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`Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence
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`of impaired fertility or harm to the fetus due to ALPHAGAN’ P. Dosing at this level produced
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`an exposure that is 189 times higher than the exposure seen in humans following multiple
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`ophthalmic doses.
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`PAGE 5 OF 7
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`PAGE 5 OF 7
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`NDA 21-262
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`Page 7
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`There are no adequate and well-controlled studies in pregnant women. In animal studies,
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`brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.
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`ALPHAGAN° P should be used during pregnancy only if the potential benefit to the mother
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`’ justifies the potential risk to the fetus.
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`Nursing Mothers:
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`It is not known whether this drug is excreted in human milk; although in animal studies
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`brimonidine tartrate was excreted in breast milk. A decision should be made whether to
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`discontinue nursing or to discontinue the drug, taking into account the importance of the drug to
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`Pediatric Use:
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`Safety and effectiveness in pediatric patients have not been established. Agitation, apnea,
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`bradycardia, convulsions, cyanosis, depression, dyspnea, emotional instability, hypotension,
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`hypothennia, hypotonia, hypoventilation, irritability, lethargy, somnolence, and stupor have been
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`reported in pediatric patients receiving brimonidine tartrate 0.2%.
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`Geriatric Use:
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`No overall differences in safety or efiectiveness have been observed between elderly and other
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`adult patients.
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`ADVERSE REACTIONS
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`Adverse events occurring in approximately 10-20% of the subjects included: allergic
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`conjunctivitis, conjunctiva! hyperernia, and eye pruritus.
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`Adverse events occurring in approximately 5-9% of the subjects includeifburning sensation,
`conjunctival folliculosis, hypertension, oral dryness, and visual disturbance.
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`Events occurring in approximately 1-4% of subjects included: allergic reaction, asthenia,
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`blepharitis, bronchitis, conjunctiva] edema, conjunctiva] hemorrhage, conjunctivitis, cough,
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`dizziness, dyspepsia, dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid
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`PAGE 6 OF 7
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`PAGE 6 OF 7
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`NDA 21-262
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`Page 8
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`edema, eyelid erythema, flu syndrome, follicular conjunctivitis, foreign body sensation, headache,
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`pharyngitis, photophobia, rash; rhinitis, sinus infection, sinusitis, stinging, superficial punctate
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`keratopathy, visual field defect, vitreous floaters, and worsened visual acuity.
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`The following events were reported in less than 1% of subjects: corneal erosion, insomnia, nasal
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`dryness, somnolence, and taste perversion.
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`OVERDOSAGE
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`No information is available on overdosage in humans. Treatment of an oral overdose includes
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`supportive and symptomatic therapy; a patent airway should be maintained.
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`DOSAGE AND ADMINISTRATION
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`The recommended dose is one drop of ALPHAGAN° P in the affected eye(s) three times daily,
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`approximately 8 hours apart.
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`HOW SUPPLIED:
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`ALPHAGAN' P is supplied sterile in opaque teal LDPE plastic bottles with droppers with
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`purple high impact polystyrene (HIPS) caps as follows:
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`5 mL in l0mL bottle
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`10 mL in 10 mL bottle
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`l5mLin15mLbottle
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`NDC 0023-9177-05
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`NDC 0023-9177-I0
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`NDC 0023-9177-15
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`NOTE: Store between 15°-25°C (59-77°F).
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`Rx Only
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`ALLERGAN
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`02000 Allergan, Inc.
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`Irvine, CA 92612, U.S.A.
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