NDA 21275/S-027
`Page 3
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to
`use LUMIGAN® 0.03% safely and effectively. See full
`prescribing information for LUMIGAN® 0.03%.
`
`LUMIGAN® (bimatoprost ophthalmic solution) 0.03%
`for topical ophthalmic use
`Initial U.S. Approval: 2001
`
`_____________RECENT MAJOR CHANGES____________
`
`Contraindications, Hypersensitivity (4)
` 07/2017
`
`_____________INDICATIONS AND USAGE_____________
`
` LUMIGAN® 0.03% is a prostaglandin analog indicated for the
`reduction of elevated intraocular pressure in patients with open
`angle glaucoma or ocular hypertension. (1)
`
`_________DOSAGE AND ADMINISTRATION___________
`One drop in the affected eye(s) once daily in the evening. (2)
`
`_________DOSAGE FORMS AND STRENGTHS_________
`Ophthalmic solution containing 0.3 mg/mL bimatoprost. (3)
`
`_______________CONTRAINDICATIONS_______________
`Hypersensitivity. (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pigmentation
`5.2 Eyelash Changes
`5.3
`Intraocular Inflammation
`5.4 Macular Edema
`5.5 Bacterial Keratitis
`5.6 Use with Contact Lenses
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`________WARNINGS AND PRECAUTIONS_____
` Pigmentation.
`Pigmentation of the iris, periorbital tissue
`(eyelid) and eyelashes can occur. Iris
`pigmentation is likely to be permanent. (5.1)
` Eyelash Changes.
`Gradual change to eyelashes including
`increased length, thickness and number of
`lashes. Usually reversible. (5.2)
`
`__________ADVERSE REACTIONS____________
`
` Most common adverse reaction is conjunctival
`hyperemia (45%). (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS,
`contact Allergan at 1-800-678-1605 or FDA at 1­
`800-FDA-1088 or www.fda.gov/medwatch.
`
`______USE IN SPECIFIC POPULATIONS_______
`Use in pediatric patients below the age of 16 years is
`not recommended because of potential safety concerns
`related to increased pigmentation following long-term
`
`chronic use. (8.4)
`
`See 17 for PATIENT COUNSELING
`INFORMATION.
`
`Revised: 07/2017
`
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing
`information are not listed.
`
`Reference ID: 4131912
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`Micro Labs v. Santen Pharm. and Asahi Glass
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`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`
`1
`
` LUMIGAN® (bimatoprost ophthalmic solution) 0.03% is indicated for the reduction of elevated intraocular
`
`pressure in patients with open angle glaucoma or ocular hypertension.
`
`
`DOSAGE AND ADMINISTRATION
`
`2
`The recommended dosage is one drop in the affected eye(s) once daily in the evening. LUMIGAN® 0.03%
`
`
`(bimatoprost ophthalmic solution) should not be administered more than once daily since it has been shown that
`
`more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect.
`
`
`Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum
`
`effect reached within approximately 8 to 12 hours.
`
`
`
`LUMIGAN® 0.03% may be used concomitantly with other topical ophthalmic drug products to lower
`
`intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered
`
`at least five (5) minutes apart.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic solution containing bimatoprost 0.3 mg/mL
`
`4
`CONTRAINDICATIONS
`LUMIGAN® 0.03% is contraindicated in patients with hypersensitivity to bimatoprost or to any of the
`
`ingredients [see Adverse Reactions (6.2)].
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Pigmentation
`5.1
`Bimatoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently
`reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes.
`Pigmentation is expected to increase as long as bimatoprost is administered. The pigmentation change is due to
`increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After
`discontinuation of bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the
`periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive
`treatment should be informed of the possibility of increased pigmentation. The long term effects of
`increased pigmentation are not known.
`
`Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around
`the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become
`more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with
`
`LUMIGAN® (bimatoprost ophthalmic solution) 0.03% can be continued in patients who develop noticeably
`increased iris pigmentation, these patients should be examined regularly [see Patient Counseling Information
`(17)].
`
`5.2
`Eyelash Changes
`LUMIGAN® 0.03% may gradually change eyelashes and vellus hair in the treated eye. These changes include
`
`
`increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation
`of treatment.
`
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`Intraocular Inflammation
`5.3
`Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. In
`addition, because these products may exacerbate inflammation, caution should be used in patients with active
`intraocular inflammation (e.g., uveitis).
`
`5.4 Macular Edema
`Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost
`
` ophthalmic solution. LUMIGAN® 0.03% should be used with caution in aphakic patients, in pseudophakic
`patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
`
`Bacterial Keratitis
`5.5
`There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical
`ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had
`
` a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information
`(17)].
`
`5.6
`Use with Contact Lenses
` LUMIGAN® 0.03% contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft
`
`contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN® 0.03% and may be
`
`reinserted 15 minutes following its administration.
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are described elsewhere in the labeling:
`• Pigmentation [see Warnings and Precautions (5.1)]
`• Eyelash Changes [see Warnings and Precautions (5.2)]
`• Intraocular Inflammation [see Warnings and Precautions (5.3)]
`• Macular Edema [see Warnings and Precautions (5.4)]
`• Hypersensitivity [see Contraindications (4)]
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`
`In clinical trials, the most frequent events associated with the use of LUMIGAN (bimatoprost ophthalmic
`
`solution) 0.03% occurring in approximately 15% to 45% of patients, in descending order of incidence, included
`conjunctival hyperemia, growth of eyelashes, and ocular pruritus. Approximately 3% of patients discontinued
`therapy due to conjunctival hyperemia.
`
`
`Ocular adverse events occurring in approximately 3 to 10% of patients, in descending order of incidence,
`included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of
`the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and
`eyelash darkening. The following ocular adverse events reported in approximately 1 to 3% of patients, in
`
`descending order of incidence, included: eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia,
`
`increases in iris pigmentation, and conjunctival edema. In less than 1% of patients, intraocular inflammation
`was reported as iritis.
`
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`NDA 21275/S-027
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` Systemic adverse events reported in approximately 10% of patients were infections (primarily colds and upper
`
`respiratory tract infections). The following systemic adverse events reported in approximately 1 to 5% of
`patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and
`hirsutism.
`
`6.2 Postmarketing Experience
`
`The following adverse reactions have been identified during postapproval use of LUMIGAN® 0.03%. Because
`
`these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
`estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been
`chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to
`LUMIGAN®, or a combination of these factors, include: abnormal hair growth, asthma-like symptoms,
`dizziness, dyspnea, eyelid edema, hypersensitivity reaction including signs and symptoms of eye allergy and
`
`allergic dermatitis, hypertension, nausea, and periorbital and lid changes including deepening of the eyelid
`sulcus.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Risk Summary
`
`There are no adequate and well-controlled studies of LUMIGAN® (bimatoprost ophthalmic solution) 0.03%
`
`
`administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based
`
`on bimatoprost postmarketing experience.
`
`
`In embryofetal developmental studies, administration of bimatoprost in pregnant mice and rats during
`organogensis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the
`human exposure at the recommended clinical dose (based on blood area under the curve [AUC] levels). These
`adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure at the
`recommended clinical dose.
`
`In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the
`end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality
`
`at oral doses at least 41 times the human systemic exposure at the recommended clinical dose (based on blood
`AUC levels). No adverse effects were observed in rat offspring at exposures estimated at 14 times the human
`exposure at the recommended clinical dose (based on blood AUC levels).
`
` Because animal reproductive studies are not always predictive of human response LUMIGAN® 0.03% should
`
`be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Data
`Animal Data
`In an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost
`orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure at the recommended
`human ophthalmic dose [RHOD], based on AUC). The No Observed Adverse Effect Level (NOAEL) for
`abortion was 0.3 mg/kg/day (estimated at 47 times the human systemic exposure at the RHOD, based on AUC).
`
`No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day.
`
`In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice
`administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times
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`NDA 21275/S-027
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`the human systemic exposure at the RHOD, based on AUC). The NOAEL for abortion and early delivery was
`0.1 mg/kg/day (2.6 times the human systemic exposure at the RHOD, based on AUC). No abnormalities were
`
`observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure at the RHOD,
`based on AUC).
`
`In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day 7 to
`lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup
`mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were
`
`observed at exposures at least 41 times the human systemic exposure at the RHOD, based on AUC. The
`NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated at
`
`14 times the human systemic exposure at the RHOD, based on AUC).
`
`Lactation
`8.2
`Risk Summary
`
`It is not known whether topical ocular treatment with LUMIGAN® 0.03% could result in sufficient systemic
`absorption to produce detectable quantities in human milk. In animal studies, bimatoprost has been shown to be
`present in breast milk of lactating rats at an intravenous dose (i.e., 1 mg/kg) 324 times the RHOD (on a m2g/m
`basis), however no animal data is available at clinically relevant doses.
`
`The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical
`
`need for LUMIGAN® 0.03% and any potential adverse effects on the breastfed child from LUMIGAN®
`
`0.03%.
`
`Pediatric Use
`8.4
`Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns
`related to increased pigmentation following long-term chronic use.
`
`8.5 Geriatric Use
`No overall clinical differences in safety or effectiveness have been observed between elderly and other adult
`patients.
`
`OVERDOSAGE
`10
`
`No information is available on overdosage in humans. If overdose with LUMIGAN® (bimatoprost ophthalmic
`
`solution) 0.03% occurs, treatment should be symptomatic.
`
`In oral (by gavage) mouse and rat general toxicity studies, doses up to 100 mg/kg/day did not produce any
`
`toxicity. This dose expressed as mg/m2 is at least 70 times higher than the accidental dose of one bottle of
`LUMIGAN® 0.03% for a 10 kg child.
`
`
`11
`DESCRIPTION
`LUMIGAN® (bimatoprost ophthalmic solution) 0.03% is a synthetic prostamide analog with ocular
`
`hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl­
`1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is
`C25H37NO4. Its chemical structure is:
`
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`Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in
`
` water. LUMIGAN® 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of
`approximately 290 mOsmol/kg.
`
`LUMIGAN® 0.03% contains Active: bimatoprost 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL;
`sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or
`
`hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive
`activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is
`believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both
`the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous
`field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.
`
`12.3 Pharmacokinetics
`Absorption: After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily to both eyes
`of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were
`below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean Cmax and
`AUC0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng•hr/mL,
`respectively, indicating that steady state was reached during the first week of ocular dosing. There was no
`significant systemic drug accumulation over time.
`
`Distribution: Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution
`of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost
`remains unbound in human plasma.
`
`
`Metabolism: Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation
`following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a
`diverse variety of metabolites.
`
`Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects,
`the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an
`elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up
`to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.
`
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`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
`Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at
`
`doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the human systemic
`exposure at the RHOD, respectively, based on blood AUC levels).
`
`Mutagenesis
`Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo
`
`mouse micronucleus tests.
`
`Impairment of Fertility
`Bimatoprost did not impair fertility in male or female rats at doses up to 0.6 mg/kg/day (at least 103 times the
`human systemic exposure at the RHOD, based on blood AUC levels).
`
`CLINICAL STUDIES
`14
`In clinical studies of patients with open angle glaucoma or ocular hypertension with a mean baseline IOP of 26
`
`mmHg, the IOP-lowering effect of LUMIGAN® 0.03% (bimatoprost ophthalmic solution) once daily (in the
`
` evening) was 7-8 mmHg.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
` LUMIGAN® (bimatoprost ophthalmic solution) 0.03% is supplied sterile in opaque white low density
`polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in the following sizes:
`2.5 mL fill in 5 mL container - NDC 0023-9187-03
`5 mL fill in 10 mL container - NDC 0023-9187-05
`7.5 mL fill in 10 mL container - NDC 0023-9187-07
`
`Storage: Store at 2°-25°C (36°-77°F).
`
`17
`
`PATIENT COUNSELING INFORMATION
`
`Potential for Pigmentation
`Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also
`inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of
`
`LUMIGAN® (bimatoprost ophthalmic solution) 0.03%.
`
`Potential for Eyelash Changes
`Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with
`LUMIGAN® 0.03%. These changes may result in a disparity between eyes in length, thickness, pigmentation,
`
`number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible
`upon discontinuation of treatment.
`
`Handling the Container
`Instruct patients to avoid allowing the tip of the dispensing container to contact the eye,
`
`surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common
`
`bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result
`
`from using contaminated solutions.
`
`
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`When to Seek Physician Advice
`Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular
`surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should
`
` immediately seek their physician’s advice concerning the continued use of LUMIGAN® 0.03%.
`
`Use with Contact Lenses
` Advise patients that LUMIGAN® 0.03% contains benzalkonium chloride, which may be absorbed by soft
`
`
`contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN® 0.03% and may be
`reinserted 15 minutes following its administration.
`
`Use with Other Ophthalmic Drugs
`Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at
`
`least five (5) minutes between applications.
`
`
`© 2017 Allergan. All rights reserved.
`
`All trademarks are the property of their respective owners.
`
`Patented. See: www.allergan.com/patents
`
`Irvine, CA 92612
`
`Made in the U.S.A.
`
`
`Reference ID: 4131912
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