NDA 18—771/8—017
`
`Page 3
`
`ATQN
`PHARMA
`
`STERILE OPHTHALMIC INSERT
`LACRISERT®
`(HYDROXYPROPYL CELLULOSE OPHTHALMIC INSERT)
`
`DESCRIPTION
`LACRISERT* (hydroxypropyl cellulose ophthalmic insert) is a sterile, translucent, rod-shaped,
`water soluble, ophthalmic insert made of hydroxypropyl cellulose, for administration into the inferior
`cul-de-sac of the eye.
`The chemical name for hydroxypropyl cellulose is cellulose, 2—hydroxypropyl ether. It is an ether of
`cellulose in which hydroxypropyl groups (—CHZCHOHCHg) are attached to the hydroxyls present in
`the anhydroglucose rings of cellulose by ether linkages. A representative structure of the monomer is:
`
`CHQOR
`
` H
`
`R
`
`R w CHZCHCHg
`OH
`
`The molecular weight is typically 1 x 106.
`Hydroxypropyl cellulose is an off-white, odorless, tasteless powder. It is soluble in water below
`38°C, and in many polar organic solvents such as ethanol, propylene glycol, dioxane, methanol,
`isopropyl alcohol (95%), dimethyl sulfoxide, and dimethyl formamide.
`Each LACRISERT is 5 mg of hydroxypropyl cellulose. LACRISERT contains no preservatives or
`other ingredients. It is about 1.27 mm in diameter by about 3.5 mm long.
`LACRISERT is supplied in packages of 60 units, together with illustrated instructions and a special
`applicator for removing LACRISERT from the unit dose blister and inserting it into the eye. A spare
`applicator is included in each package.
`
`*Registered trademark of ATON PHARMA, INC.
`COPYRIGHT © ATON PHARMA, INC., 2007
`All rights reserved
`
`APOTEX 1064, pg. 1
`
`APOTEX 1064, pg. 1
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`NDA 18-771/8—017
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`Page 4
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`CLINICAL PHARMACOLOGY
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`Pharmacodynamics
`
`LACRISERT acts to stabilize and thicken the precorneal tear film and prolong the tear film breakup
`time which is usually accelerated in patients with dry eye states. LACRISERT also acts to lubricate
`and protect the eye.
`LACRISERT usually reduces the signs and symptoms resulting from moderate to severe dry eye
`syndromes, such as conjunctival hyperemia, corneal and conjunctival staining with rose bengal,
`exudation, itching, burning, foreign body sensation, smarting, photophobia, dryness and blurred or
`cloudy vision. Progressive visual deterioration which occurs in some patients may be retarded, halted,
`or sometimes reversed.
`In a multicenter crossover study the 5 mg LACRISERT administered once a day during the waking
`hours was compared to artificial tears used four or more times daily. There was a prolongation of tear
`film breakup time and a decrease in foreign body sensation associated with dry eye syndrome in
`patients during treatment with inserts as compared to artificial tears; these findings were statistically
`significantly different between the treatment groups. Improvement, as measured by amelioration of
`symptoms, by slit lamp examination and by rose bengal staining of the cornea and conjunctiva, was
`greater in most patients with moderate to severe symptoms during treatment with LACRISERT.
`Patient comfort was usually better with LACRISERT than with artificial tears solution, and most
`patients preferred LACRISERT.
`In most patients treated with LACRISERT for over one year, improvement was observed as
`evidenced by amelioration of symptoms generally associated with keratoconjunctivitis sicca such as
`burning, tearing, foreign body sensation, itching, photophobia and blurred or cloudy vision.
`During studies in healthy volunteers, a thickened precorneal tear film was usually observed through
`the slit—lamp while LACRISERT was present in the conjunctival sac.
`
`Pharmacokinetics and Metabolism
`Hydroxypropyl cellulose is a physiologically inert substance. In a study ofrats fed hydroxypropyl
`cellulose or unmodified cellulose at levels up to 5% oftheir diet, it was found that the two were
`biologically equivalent in that neither was metabolized.
`Studies conducted in rats fed 14C-labeled hydroxypropyl cellulose demonstrated that when orally
`administered, hydroxypropyl cellulose is not absorbed from the gastrointestinal tract and is
`quantitatively excreted in the feces.
`Dissolution studies in rabbits showed that hydroxypropyl cellulose inserts became softer within 1
`hour after they were placed in the conjunctiva! sac. Most ofthe inserts dissolved completely in 14 to
`18 hours; with a single exception, all had disappeared by 24 hours after insertion. Similar dissolution
`of the inserts was observed during prolonged administration (up to 54 weeks).
`
`INDICATIONS AND USAGE
`
`LACRISERT is indicated in patients with moderate to severe dry eye syndromes, including
`keratoconjunctivitis sicca. LACRISERT is indicated especially in patients who remain symptomatic
`after an adequate trial of therapy with artificial tear solutions.
`
`LACRISERT is also indicated for patients with:
`Exposure keratitis
`Decreased corneal sensitivity
`Recurrent corneal erosions
`
`APOTEX 1064, pg. 2
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`APOTEX 1064, pg. 2
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`NDA 18—77l/S-017
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`Page 5
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`CONTRAINDICATIONS
`
`LACRISERT is contraindicated in patients who are hypersensitive to hydroxypropyl cellulose.
`
`WARNINGS
`
`Instructions for inserting and removing LACRISERT should be carefully followed.
`
`PRECAUTIONS
`
`General
`
`If improperly placed, LACRISERT may result in corneal abrasion (see DOSAGE AND
`ADMINISTRATION). Information for Patients
`Patients should be advised to follow the instructions for using LACRISERT which accompany the
`
`package.
`Because this product may produce transient blurring of vision, patients should be instructed to
`exercise caution when operating hazardous machinery or driving a motor vehicle.
`
`Drug Interactions
`Application of hydroxypropyl cellulose ophthalmic inserts to the eyes of unanesthetized rabbits
`immediately prior to or two hours before instilling pilocarpine, proparacaine HCl (0.5%), or
`phenylephrine (5%) did not markedly alter the magnitude and/or duration of the miotic, local corneal
`anesthetic, or mydriatic activity, respectively, of these agents. Under various treatment schedules, the
`anti-inflammatory effect of ocularly instilled dexamethasone (0.1%) in unanesthetized rabbits with
`primary uveitis was not affected by the presence of hydroxypropyl cellulose inserts.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Feeding of hydroxypropyl cellulose to rats at levels up to 5% of their diet produced no gross or
`histopathologic changes or other deleterious effects.
`
`Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use
`
`No overall differences in safety or effectiveness have been observed between elderly and younger
`patients.
`
`ADVERSE REACTIONS
`
`The following adverse reactions have been reported in patients treated with LACRISERT, but were
`in most instances mild and transient:
`
`Transient blurring of vision (See PRECAUTIONS)
`Ocular discomfort or irritation
`
`Matting or stickiness of eyelashes
`Photophobia
`Hypersensitivity
`Edema of the eyelids
`Hyperemia
`
`APOTEX 1064, pg. 3
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`APOTEX 1064, pg. 3
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`NDA l8—77l/S—017
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`Page 6
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`DOSAGE AND ADMINISTRATION
`
`One LACRISERT ophthalmic insert in each eye once daily is usually sufficient to relieve the
`symptoms associated with moderate to severe dry eye syndromes. Individual patients may require
`more flexibility in the use of LACRISERT; some patients may require twice daily use for optimal
`results.
`Clinical experience with LACRISERT indicates that in some patients several weeks may be required
`before satisfactory improvement of symptoms is achieved.
`LACRISERT is inserted into the inferior cul—de—sac of the eye beneath the base of the tarsus, not in
`apposition to the cornea, nor beneath the eyelid at the level of the tarsal plate. If not properly
`positioned, it will be expelled into the interpalpebral fissure, and may cause symptoms ofa foreign
`body. Illustrated instructions are included in each package. While in the licensed practitioner’s office,
`the patient should read the instructions, then practice insertion and removal of LACRISERT until
`proficiency is achieved.
`NOTE: Occasionally LACRISERT is inadvertently expelled from the eye, especially in patients with
`shallow conjunctival fornices. The patient should be cautioned against rubbing the eye(s) containing
`LACRISBRT, especially upon awakening, so as not to dislodge or expel the insert. If required, another
`LACRISERT ophthalmic inseit may be inserted. If experience indicates that transient blurred vision
`develops in an individual patient, the patient may want to remove LACRISERT a few hours after
`insertion to avoid this. Another LACRISERT ophthalmic insert maybe inserted if needed.
`If LACRISERT causes worsening of symptoms, the patient should be instructed to inspect the
`conjunctival sac to make certain LACRISERT is in the proper location, deep in the inferior cul-de—sac
`of the eye beneath the base of the tarsus. If these symptoms persist, LACRISERT should be removed
`and the patient should contact the practitioner.
`
`HOW SUPPLIED
`LACRISERT, a sterile, translucent, rod—shaped, water—soluble, ophthalmic insert made of
`hydroxypropyl cellulose, 5 mg, is supplied as follows:
`NDC 25010—805—68 in packages containing 60 unit doses (each wrapped in an aluminum blister),
`two reusable applicators, and a plastic storage container to store the applicators after use.
`
`Storage
`Store below 30°C (86°F).
`
`W D
`
`istributed by:
`ATON PHARMA, INC.
`Lawrenceville, NJ 08648, USA
`
`Manufactured by:
`Merck and Co., Inc.
`West Point, PA 19486 USA
`
`Issued June 2007
`Printed in USA
`
`APOTEX 1064, pg. 4
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`APOTEX 1064, pg. 4
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`NDA 18-77l/S-017
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`Page 7
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`INSTRUCTIONS FOR USING
`LACRISERT®
`(HYDROXYPROPYL CELLULOSE OPHTHALMIC INSERT)
`
`Note: Your licensed practitioner or a trained associate can demonstrate the proper use of
`LACRISERT*. Please read and follow these instructions carefully for your subsequent use.
`
`Clinical experience with LACRISERT indicates that in some patients several weeks may be required
`before satisfactory improvement of symptoms is achieved.
`
`Two applicators (one spare) are supplied with each package.
`
`Before opening the package of LACRISERT, wash your hands thoroughly with soap and water.
`
`9
`
`STEP 1: On a flat surface, open blister pocket slowly and smoothly by peeling back label area. Each
`blister pocket contains one LACRISERT ophthalmic insert.
`
`Q
`
`STEP 2: Open applicator package with label side up. Avoid touching grooved tip of the applicator.
`Pick up applicator by the wide end and rinse the tip thoroughly under hot running tap water. Gently
`shake off excess water.
`
`APOTEX 1064, pg. 5
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`APOTEX 1064, pg. 5
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`NDA 18-771/S—017
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`STEP 3: Hold applicator with tip facing down and with forefinger on top to guide and apply gentle
`pressure. Lightly press the grooved tip of the applicator onto the LACRISERT ophthalmic insert and it
`will adhere to the applicator.
`
`It is important to follow STEPS 4 and 5 carefully or you might experience difficulty in keeping
`LACRISERT (hydroxypropyl cellulose ophthalmic insert) in your eye.
`
`STEP 4: Look into a mirror. Starting with the right eye, turn your head to the right so that the colored
`part of the eye is close to your nose. Use your free hand to grasp the lower lid between the thumb and
`index finger. Pull the lid away from the eyeball and create a pocket between the white part of the
`eyeball and the lid.
`
`
`
`STEP 5: Place the tip of the applicator containing LACRISERT into the pocket. Avoid touching the
`colored part of the eye.
`
`Remove the applicator. It is important, after removing the applicator, to look down, then release
`the lower eyelid. LACRISERT (hydroxypropyl cellulose ophthalmic insert) should remain deep
`in the lower pocket recess of the eye and not near the lower eyelid.
`
`Repeat procedure with left eye, turning head to the left so that the colored part of the eye is close to
`your nose.
`
`APOTEX 1064, pg. 6
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`APOTEX 1064, pg. 6
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`NDA 18-771/8—017
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`Page 9
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`Rinse the applicator thoroughly under hot running tap water after use. Gently shake off visible water
`droplets and promptly return it to the storage container. Note that the storage container provides space
`for a strip of two LACRISERT ophthalmic inserts next to the applicator storage compartment.
`
`IlVIPORTANT
`If LACRISERT causes worsening of symptoms: or if new symptoms develop: it should be removed
`and your prescriber contacted.
`
`Should the removal of the LACRISERT ophthalmic insert be necessary, follow these instructions.
`1. Locate LACRISERT by pulling the lid away from the eyeball while looking for LACRISERT
`in a mirror.
`
`2. Then close the eyelids.
`3. When located, move LACRISERT upward with your fingers through the closed eyelids.
`4. Keep the lids against the eyeball and LACRISERT should slip over the lid margin so that you
`can remove it with a clean facial tissue without touching the colored part of the eye.
`
`CAUTION: Because this product may produce transient blurring of vision, you should exercise
`caution when operating hazardous machinery or driving a motor vehicle.
`
`Store below 30°C (86°F).
`
`Issued May 2007
`
`ATON PHARMA, INC.
`LAWRENCEVILLE, NJ 08648, USA
`
`APOTEX 1064, pg. 7
`
`APOTEX 1064, pg. 7
`
`