OCUSERT® pilocarpine system is an elliptically shaped unit designed for continuous release of pilocarpine following placement in the cul-de-sac of the eye. Clinical evaluation in appropriate patients has demonstrated therapeutic efficacy of the system in the eye for one week. Two strengths are available, Pilo-20 and Pilo-40.

OCUSERT® systems contain a core reservoir consisting of pilocarpine and alginic acid. Pilocarpine is designated chemically as 2(3H)-Furanone,3-ethyldihydro-4[(1-methyl-1H-imidazol-5-yl) methyl]-, (3S-cis)- and has the following structural formula:

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The core is surrounded by a hydrophobic ethylene/vinyl acetate (EVA) copolymer membrane which controls the diffusion of pilocarpine from the OCUSERT® system into the eye. The Pilo-40 membrane contains di(2-ethylhexyl) phthalate, which increases the rate of diffusion of pilocarpine across the EVA membrane. Of the total content of pilocarpine in the Pilo-20 or Pilo-40 system (5 mg or 11 mg, respectively), a portion serves as the thermodynamic diffusional energy source to release the drug and remains in the unit at the end of the week's use. The alginic acid component of the core is not released from the system. The readily visible white margin around the system contains titanium dioxide. The Pilo-20 system is 5.7 × 13.4 mm on its axes and 0.3 mm thick; the Pilo-40 system is 5.5 × 13 mm on its axes and 0.5 mm thick.

Release Rate Concept:   With the OCUSERT® system form of therapy, the particular strength is described by the rated release, the mean release rate of drug from the system over seven days, in micrograms per hour. To cover the range of drug therapy needed to control the increased intraocular pressure associated with the glaucomas, two rated releases of pilocarpine from the OCUSERT® system are available, 20 and 40 micrograms per hour, for one week.

During the first few hours of the seven day time course, the release rate is higher than that prevailing over the remainder of the one-week period. The system releases drug at three times the rated value in the first hours and drops to the rated value in approximately six hours. A total of 0.3 mg to 0.7 mg pilocarpine (Pilo-20 or Pilo-40, respectively) is released during this initial six-hour period (one drop of 2% pilocarpine ophthalmic solution contains 1 mg pilocarpine). During the remainder of the seven day period the release rate is within ± 20% of the rated value.

Clinical Pharmacology:   Pilocarpine is released from the OCUSERT® system as soon as it is placed in contact with the conjunctival surfaces. Pilocarpine is a direct acting parasympathomimetic drug which produces pupillary constriction, stimulates the ciliary muscle, and increases aqueous humor outflow facility. Because of its action on ciliary muscle, pilocarpine induces transient myopia, generally more pronounced in younger patients. In association with the increase in outflow facility, there is a decrease in intraocular pressure.

Preclinical Results:   The levels of 14 C-pilocarpine in the ocular tissues of rabbits following OCUSERT® system and eyedrop administration have been determined. The OCUSERT® system produces constant low pilocarpine levels in the ciliary body and iris. Following 14 C-pilocarpine eyedrop treatment, the initial levels of pilocarpine in the cornea, aqueous humor, ciliary body and iris are 3 to 5 times higher than the corresponding levels with the OCUSERT® system, declining over the next six hours to approximately the tissue concentrations maintained by the OCUSERT® system. In contrast, in the conjunctiva, lens, and vitreous the 14 C-pilocarpine concentrations remain consistently high from eyedrops and do not return to the constant low levels maintained by the OCUSERT® system. Pilocarpine does not accumulate in ocular tissues during OCUSERT® system use. These studies in rabbits have not been done in humans.

Clinical Results:   The ocular hypotensive effect of both the Pilo-20 and Pilo-40 systems is fully developed within 1 ½ to 2 hours after placement in the cul-de-sac. A satisfactory ocular hypotensive response is maintained around-the-clock. Intraocular pressure reduction for an entire week is achieved with the OCUSERT® system from either 3.4 mg or 6.7 mg pilocarpine (20 or 40 µg/hour times 24 hours/day times 7 days, respectively), as compared with 28 mg administered as a 2% ophthalmic solution four times a day.

During the first several hours after insertion of an OCUSERT® pilocarpine system into the conjunctival cul-de-sac, induced myopia may occur. In contrast to the fluctuating and high levels of induced myopia typical of pilocarpine administration by eyedrop, the amount of induced myopia with OCUSERT® systems decreases after the first several hours to a low baseline level, approximately 0.5 diopters or less, which persists for the therapeutic life of the OCUSERT® system. Pilocarpine-induced miosis approximately parallels the induced myopia.

Of the 302 patients who used the OCUSERT® system in clinical studies for more than two weeks, 229 (75%) preferred it to previously used pilocarpine eyedrops. This percentage increased with further wearing experience.

and Usage:   OCUSERT® pilocarpine system is indicated for control of elevated intraocular pressure in pilocarpine responsive patients. Clinical studies have demonstrated OCUSERT® system efficacy in certain glaucomatous patients.

The patient should be instructed on the use of the OCUSERT® system and should read the package insert instructions for use. The patient should demonstrate to the ophthalmologist his ability to place, adjust and remove the units.

Concurrent Therapy:   OCUSERT® systems have been used concomitantly with various ophthalmic medications. The release rate of pilocarpine from the OCUSERT® system is not influenced by carbonic anhydrase inhibitors, epinephrine or timolol ophthalmic solutions, fluorescein, or anesthetic, antibiotic, or anti-inflammatory steroid ophthalmic solutions. Systemic reactions consistent with an increased rate of absorption from the eye of an autonomic drug, such as epinephrine, have been observed. The occurrence of mild bulbar conjunctival edema, which is frequently present with epinephrine ophthalmic solutions, is not influenced by the OCUSERT® pilocarpine system.

Contraindications:   OCUSERT® pilocarpine system is contraindicated where pupillary constriction is undesirable, such as for glaucomas associated with acute inflammatory disease of the anterior segment of the eye, and glaucomas occurring or persisting after extracapsular cataract extraction where posterior synechiae may occur.

:   Patients with acute infectious conjunctivitis or keratitis should be given special consideration and evaluation prior to the use of the OCUSERT® pilocarpine system.

Damaged or deformed systems should not be placed or retained in the eye. Systems believed to be associated with an unexpected increase in drug action should be removed and replaced with a new system.

Precautions:

General

OCUSERT® pilocarpine system safety in retinal detachment patients and in patients with filtration blebs has not been established. The conjunctival erythema and edema associated with epinephrine ophthalmic solutions are not substantially altered by concomitant OCUSERT® pilocarpine system therapy. The use of pilocarpine drops should be considered when intense miosis is desired in certain ocular conditions.

Drug Interactions

Although ophthalmic solutions have been used effectively in conjunction with the OCUSERT® system, systemic reactions consistent with an increased rate of absorption from the eye of an autonomic drug, such as epinephrine, have been observed. In rare instances, reactions of this type can be severe.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term carcinogenicity and reproduction studies in animals have been conducted with the OCUSERT® system.

Pregnancy Category C

Although the use of the OCUSERT® pilocarpine system has not been reported to have adverse effect on pregnancy, the safety of its use in pregnant women has not been absolutely established. While systemic absorption of pilocarpine from the OCUSERT® system is highly unlikely, pregnant women should use it only if clearly needed.

Nursing Mothers

It is not known whether pilocarpine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when the OCUSERT® system is used by a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

Adverse Reactions:   Ciliary spasm is encountered with pilocarpine usage but is not a contraindication to continued therapy unless the induced myopia is debilitating to the patient. Irritation from pilocarpine has been infrequently encountered and may require cessation of therapy depending on the judgement of the physician. True allergic reactions are uncommon but require discontinuation of therapy should they occur. Corneal abrasion and visual impairment have been reported with use of the OCUSERT® System.

Although withdrawal of the peripheral iris from the anterior chamber angle by miosis may reduce the tendency for narrow angle closure, miotics can occasionally precipitate angle closure by increasing the resistance to aqueous flow from posterior to anterior chamber. Miotic agents may also cause retinal detachment; thus, care should be exercised with all miotic therapy especially in young myopic patients.

Some patients may notice signs of conjunctival irritation, including mild erythema with or without a slight increase in mucous secretion when they first use OCUSERT® pilocarpine systems. These symptoms tend to lessen or disappear after the first week of therapy. In rare instances a sudden increase in pilocarpine effects has been reported during system use.

Dosage and Administration: Initiation of Therapy:   A patient whose intraocular pressure has been controlled by 1% or 2% pilocarpine eyedrop solution has a higher probability of pressure control with the Pilo-20 system than a patient who has used a higher strength pilocarpine solution and might require Pilo-40 therapy. However, there is no direct correlation between the OCUSERT® system (Pilo-20 or Pilo-40) and the strength of pilocarpine eyedrop solutions required to achieve a given level of pressure lowering. The OCUSERT® system reduces the amount of drug necessary to achieve adequate medical control; therefore, therapy may be started with the OCUSERT® Pilo-20 system irrespective of the strength of pilocarpine solution the patient previously required. Because of the patient' age, family history, and disease status or progression, however, the ophthalmologist may elect to begin therapy with the Pilo-40. The patient should then return during the first week of therapy for evaluation of his intraocular pressure, and as often thereafter as the ophthalmologist deems necessary.

If the pressure is satisfactorily reduced with the OCUSERT® Pilo-20 system the patient should continue its use, replacing each unit every 7 days. If the physician desires intraocular pressure reduction greater than that achieved by the Pilo-20 system, the patient should be transferred to the Pilo-40 system. If necessary, an epinephrine ophthalmic solution or a carbonic anhydrase inhibitor may be used concurrently with OCUSERT® system.

After a satisfactory therapeutic regimen has been established with the OCUSERT® pilocarpine system, the frequency of follow-up should be determined by the ophthalmologist according to the status of the patient' disease process.

Placement and Removal of the OCUSERT® System: The OCUSERT® system is readily placed in the eye by the patient, according to patient instructions provided in the package. The instructions also describe procedures for removal of the system. It is strongly recommended that the patient' ability to manage the placement and removal of the system be reviewed at the first patient visit after initiation of therapy.

Since the pilocarpine-induced myopia from the OCUSERT® systems may occur during the first several hours of therapy (average of 1.4 diopters in a group of young subjects), the patient should be advised to place the system into the conjunctial cul-de-sac at bedtime. By morning the induced myopia is at a stable level (about 0.5 diopters or less in young subjects).

Sanitary Handling:   Patients should be instructed to wash their hands thoroughly with soap and water before touching or manipulating the OCUSERT® system. In the event a displaced unit contacts unclean surfaces, rinsing with cool tap water before replacing is advisable. Obviously bacteriologically contaminated units should be discarded and replaced with a fresh unit.

OCUSERT® System Retention in the Eye: During the initial adaptation period, the OCUSERT® unit may slip out of the conjunctival cul-de-sac onto the cheek. The patient is usually aware of such movement and can replace the unit without difficulty.

In those patients in whom retention of the OCUSERT® unit is a problem, superior cul-de-sac placement is often more desirable. The OCUSERT® unit can be manipulated from the lower to the upper conjunctival cul-de-sac by a gentle digital massage through the lid, a technique readily learned by the patient. If possible the unit should be moved before sleep to the upper conjunctival cul-de-sac for best retention. Should the unit slip out of the conjunctival cul-de-sac during sleep, its ocular hypotensive effect following loss continues for a period of time comparable to that following instillation of eyedrops. The patient should be instructed to check for the presence of the OCUSERT® unit before retiring at night and upon arising.

How Supplied:   OCUSERT® Pilo-20 or Pilo-40 systems are available in packages containing eight individual sterile systems.

Storage and Handling:   Store under refrigeration (36°-46°F).

Rx only

MANUFACTURED FOR:

AKORN, Inc., Buffalo Grove, IL 60089

BY:

ALZA Corporation, Palo Alto, California 94304

Edition Date: September 1998

7140641-7

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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