Pilocarpine Hydrochloride

1 INDICATIONS AND USAGE Pilocarpine hydrochloride ophthalmic solution is indicated for the: Pilocarpine hydrochloride ophthalmic solution is a muscarinic cholinergic agonist indicated for: • The reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. ( 1.1 ) • The management of acute angle-closure glaucoma. ( 1.2 ) • The prevention of postoperative elevated IOP associated with laser surgery. ( 1.3 ) • The induction of miosis. ( 1.4 ) 1.1 Reduction of Elevated Intraocular Pressure (IOP) in Patients With Open-Angle Glaucoma or Ocular Hypertension . 1.2 Management of Acute Angle-Closure Glaucoma . 1.3 Prevention of Postoperative Elevated IOP Associated With Laser Surgery . 1.4 Induction of Miosis .

2 DOSAGE AND ADMINISTRATION Instill one drop in the eye(s) up to four times daily (2). 2.1 Reduction of Elevated Intraocular Pressure (IOP) in Patients with Open-Angle Glaucoma or Ocular Hypertension One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% should be applied topically in the eye(s) up to four times daily. Pilocarpine-naïve patients should be started on the 1% concentration as higher concentrations are often not tolerated initially. The frequency of instillation and concentration of pilocarpine hydrochloride ophthalmic solution are determined by the severity of the elevated intraocular pressure and miotic response of the patient. To limit systemic exposure to pilocarpine, patients may be instructed to perform punctal occlusion for 2 minutes after instillation of pilocarpine hydrochloride ophthalmic solution. 2.2 Management of Acute Angle-Closure Glaucoma Prior to pilocarpine hydrochloride ophthalmic solution use, treatment with secretory suppressants and hyperosmotic agents may be needed to lower IOP below 50 mmHg and relieve iris ischemia. For initial management of acute angle-closure glaucoma, one drop of pilocarpine hydrochloride ophthalmic solution 1% or 2% may be applied topically in the eye(s) up to three times over a 30-minute period. If laser iridoplasty or iridomy is used to break the attack, one drop of pilocarpine hydrochloride ophthalmic solution 4% should be administered prior to the procedure. Following laser iridoplasty, one drop of pilocarpine hydrochloride ophthalmic solution 1% should be administered four times daily until an iridotomy can be performed. 2.3 Prevention of Postoperative Elevated IOP Associated with Laser Surgery One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s) 15 to 60 minutes prior to surgery. 2.4 Induction of Miosis One drop of pilocarpine hydrochloride ophthalmic solution 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s). 2.5 Use with Other Topical Ophthalmic Medications Pilocarpine hydrochloride ophthalmic solution may be used in combination with beta-blockers, carbonic anhydrase inhibitors, sympathomimetics or hyperosmotic agents. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. 2.6 Use in Pediatric Patients In children under 2 years of age, one drop of pilocarpine hydrochloride ophthalmic solution 1% should be applied topically in the eye(s) three times daily. Children 2 years of age and over should be dosed as for adults. For the induction of miosis prior to goniotomy or trabeculotomy in children, one drop of pilocarpine hydrochloride ophthalmic solution 1% or 2% should be applied topically in the eye 15 to 60 minutes prior to surgery.

3 DOSAGE FORMS AND STRENGTHS Bottle filled with 15 mL of 1% (10 mg/mL), 2% (20 mg/mL) or 4% (40 mg/mL) pilocarpine hydrochloride, USP sterile ophthalmic solution. Solution containing 1% (10 mg/mL), 2% (20 mg/mL) or 4% (40 mg/mL) pilocarpine hydrochloride. (3)

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS Clinical Studies Experience 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. The safety data described below reflect exposure in four controlled clinical trials of 90 days to 2 years duration in 317 patients diagnosed with open-angle glaucoma or ocular hypertension. In the four clinical trials, patients were treated with pilocarpine hydrochloride ophthalmic solution 2%, two to four times daily or with pilocarpine 1%, 1.75% or 2% in fixed combination with betaxolol 0.25%, two or three times daily. The most frequently reported adverse reactions occurring in ≥ 5% of patients in the pilocarpine 2% populations were: headache/browache, accommodative change, blurred vision, eye irritation, visual impairment (dim, dark, or "jumping" vision), and eye pain. The adverse reaction profile reported for the use of pilocarpine hydrochloride ophthalmic solution in pediatric patients is comparable to that seen in adult patients. Most common adverse reactions are headache/browache, accommodative change, eye irritation, eye pain, blurred vision, and/or visual impairment (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy. Category C. Animal reproduction studies have not been conducted with pilocarpine hydrochloride. It is also not known whether pilocarpine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pilocarpine hydrochloride ophthalmic solution should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when pilocarpine hydrochloride ophthalmic solution is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of pilocarpine hydrochloride ophthalmic solution in pediatric patients have been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.

12.1 Mechanism of Action Pilocarpine hydrochloride is a direct acting cholinergic parasympathomimetic agent which acts through direct stimulation of muscarinic receptors and smooth muscle such as the iris and secretory glands. Pilocarpine contracts the ciliary muscle, causing increased tension on the scleral spur and opening of the trabecular meshwork spaces to facilitate outflow of aqueous humor. Outflow resistance is reduced, lowering intraocular pressure (IOP). Pilocarpine also produces miosis through contraction of the iris sphincter muscle. Miosis relieves appositional angle narrowing and closure, which lowers IOP in certain types of angle-closure glaucoma.

11 DESCRIPTION Pilocarpine hydrochloride ophthalmic solution, USP is a cholinergic agonist prepared as a sterile topical ophthalmic solution. The active ingredient is represented by the chemical structure: Established Name: pilocarpine hydrochloride, USP Chemical Name: 2(3 H )-furanone, 3-ethyldihydro-4-[(1-methyl-1 H -imidazol-5-yl)-methyl]-monohydrochloride, (3S- cis ). Molecular Formula: C 11 H 16 N 2 O 2 • HCl Molecular Weight: 244.72 Pilocarpine hydrochloride, USP is a white or almost white, crystalline powder or colorless crystals hygroscopic. It is very soluble in water, freely soluble in alcohol, slightly soluble in chloroform and insoluble in ether. Each mL of pilocarpine hydrochloride ophthalmic solution, USP contains: Active: pilocarpine hydrochloride, USP 1% (10 mg/mL), 2% (20 mg/mL), or 4% (40 mg/mL). Preservative: benzalkonium chloride 0.01%. Inactives: 0.5% hypromellose 2910; boric acid; sodium citrate; sodium chloride (present in 1% product only); hydrochloric acid and/or sodium hydroxide (to adjust pH); water for injection. Pilocarpine hydrochloride ophthalmic solution, USP has a pH of 3.5 to 5.5 and an osmolality of 270 to 350 mOsm/kg (1% product), 290 to 350 mOsm/kg (2% product) and 500 to 600 mOsm/kg (4% product). ab

10 OVERDOSAGE Systemic toxicity following topical ocular administration of pilocarpine is rare, but occasionally patients who are sensitive may develop sweating and gastrointestinal overactivity following the suggested dosage and administration. Overdosage can produce sweating, salivation, nausea, tremors and slowing of the pulse and a decrease in blood pressure. In moderate overdosage, spontaneous recovery is to be expected and is aided by intravenous fluids to compensate for dehydration. For patients demonstrating severe poisoning, atropine, the pharmacologic antagonist to pilocarpine, should be used.

16 HOW SUPPLIED/STORAGE AND HANDLING Pilocarpine hydrochloride ophthalmic solution 1%, 2%, and 4% is supplied sterile in natural low density polyethylene plastic ophthalmic dispensers and green low density polyethylene tips with green polypropylene caps. 15 mL in 15 mL bottles 1%: NDC 61314-203-15 2%: NDC 61314-204-15 4%: NDC 61314-206-15 STORAGE: Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from freezing.