ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. 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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 years duration in 317 patients diagnosed with open-angle glaucoma or ocular hypertension. In the four clinical trials, patients were treated with Isopto(R) Carpine 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/brow ache, 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 Isopto(R) Carpine in pediatric patients is comparable to that seen in adult patients.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. There have been no long-term studies done using pilocarpine hydrochloride in animals to evaluate carcinogenic potential.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Pilocarpine hydrochloride is 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 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.. 12.3Pharmacokinetics. Systemic exposure to pilocarpine was evaluated in 14 healthy subjects administered drops of Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) 4% to both eyes four times daily for eight days. comparison of Cmax values on Days and indicated that pilocarpine concentrations in plasma reached steady-state following topical administration of Isopto(R) Carpine 4%. The mean (SD) Cmax and AUC0-last values on Day were 3.7 (3.2) ng/mL and 7.7 (8.4) ngxhour/mL, respectively. The Tmax values on Day ranged from 0.5 to hour.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. In clinical trials reported in the medical literature, pilocarpine ophthalmic solution reduced IOP by 3-7 mmHg in patients with open-angle glaucoma. Pilocarpine ophthalmic solution has also been shown to be effective in the induction of miosis, in the prevention of postoperative elevated IOP, and in the management of acute angle-closure glaucoma.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 years duration in 317 patients diagnosed with open-angle glaucoma or ocular hypertension. In the four clinical trials, patients were treated with Isopto(R) Carpine 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/brow ache, 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 Isopto(R) Carpine in pediatric patients is comparable to that seen in adult patients.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11DESCRIPTION. Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) is cholinergic agonist prepared as sterile topical ophthalmic solution. The active ingredient is represented by the chemical structure:Established name: pilocarpine hydrochlorideChemical name: 2(3H)-furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)-methyl]-monohydrochloride, (3S-cis)-. Molecular Formula: C11H16N2O2 HCl; Molecular Weight: 244.72 g/mol.Each mL of Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) contains: Active: pilocarpine hydrochloride 1% (10 mg/mL), 2% (20 mg/mL), or 4% (40 mg/mL).Preservative: benzalkonium chloride 0.01%.Inactives: hypromellose 2910, boric acid, sodium citrate, sodium chloride (present in 1% only); hydrochloric acid and/or sodium hydroxide (to adjust pH); purified water. Isopto(R) Carpine has pH of 3.5 to 5.5 and an osmolality of 290 to 350 mOsm/kg (1% and 2% products) and 550 to 600 mOsm/kg (4% product).

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Instill one drop in the eye(s) up to four times daily. (2). Instill one drop in the eye(s) up to four times daily. (2). 2.1Reduction of Elevated IOP in Patients With Open-Angle Glaucoma or Ocular Hypertension. One drop of Isopto(R) Carpine 1%, 2%, or 4% should be applied topically in the eye(s) up to four times daily. Pilocarpine-naive patients should be started on the 1% concentration as higher concentrations are often not tolerated initially. The frequency of instillation and concentration of Isopto(R) Carpine 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 minutes after instillation of Isopto(R) Carpine ophthalmic solution.. 2.2Management of Acute Angle-Closure Glaucoma. Prior to Isopto(R) Carpine 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 Isopto(R) Carpine 1% or 2% may be applied topically in the eye(s) up to three times over 30-minute period.If laser iridoplasty or iridomy is used to break the attack, one drop of Isopto(R) Carpine 4% should be administered prior to the procedure. Following laser iridoplasty, one drop of Isopto(R) Carpine 1% should be administered four times daily until an iridotomy can be performed.. 2.3Prevention of Postoperative Elevated IOP Associated With Laser Surgery. One drop of Isopto(R) Carpine 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.. 2.4Induction of Miosis. One drop of Isopto(R) Carpine 1%, 2%, or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s).. 2.5Use With Other Topical Ophthalmic Medications. Isopto(R) Carpine 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 minutes apart.. 2.6Use in Pediatric Patients. In children under years of age, one drop of Isopto(R) Carpine 1% should be applied topically in the eye(s) three times daily. Children 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 Isopto(R) Carpine 1% or 2% should be applied topically in the eye 15 to 60 minutes prior to surgery.

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

8.5Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) 1%, 2%, and 4% is supplied sterile in natural low density polyethylene plastic ophthalmic (R)dispensers and green low density polyethylene tips with green polypropylene caps.15 mL in 15 mL bottles1%: NDC 0998-0203-152%: NDC 0998-0204-154%: NDC 0998-0206-15STORAGE: Store at 20C to 25C (68 to 77F), excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Protect from freezing.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. Isopto(R) Carpine is indicated for the:. Isopto Carpine is 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). 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). 1.1Reduction of Elevated Intraocular Pressure (IOP) in Patients With Open-Angle Glaucoma or Ocular Hypertension. 1.2Management of Acute Angle-Closure Glaucoma. 1.3Prevention of Postoperative Elevated IOP Associated With Laser Surgery. 1.4Induction of Miosis.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Avoiding Contamination of the ProductDo not touch dropper tip to any surface, as this may contaminate the contents.Night DrivingCaution is advised with night driving and when hazardous activities are undertaken in poor illumination.Accommodative SpasmIsopto(R) Carpine ophthalmic solution may cause problems when changing focus between near objects and distant objects. Do not drive or use machinery if vision is not clear.Contact Lens WearContact lens should be removed prior to the instillation of Isopto(R) Carpine ophthalmic solution. Wait 10 minutes after dosing before reinserting contact lenses.Concomitant Topical Ocular TherapyIf more than one topical ophthalmic medication is being used, the medicines must be administered at least minutes apart.Systemic ExposureTo limit exposure to pilocarpine to the eye alone, close eyes gently and apply pressure with finger to the corner of eye by the nose for minutes after instillation of Isopto(R) Carpine ophthalmic solution.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2020-78.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Pilocarpine hydrochloride is 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 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.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. There have been no long-term studies done using pilocarpine hydrochloride in animals to evaluate carcinogenic potential.

NURSING MOTHERS SECTION.

8.3Nursing 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 Isopto(R) Carpine is administered to nursing woman.

OVERDOSAGE SECTION.

10OVERDOSAGE. 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0998-0203-15 Alcon(R) Isopto(R) Carpine 1%(pilocarpine hydrochloride ophthalmic solution) 15 mL Sterile Rx Only. Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) 1%.

PEDIATRIC USE SECTION.

8.4Pediatric Use. Safety and effectiveness of pilocarpine hydrochloride ophthalmic solution in pediatric patients have been established.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Systemic exposure to pilocarpine was evaluated in 14 healthy subjects administered drops of Isopto(R) Carpine (pilocarpine hydrochloride ophthalmic solution) 4% to both eyes four times daily for eight days. comparison of Cmax values on Days and indicated that pilocarpine concentrations in plasma reached steady-state following topical administration of Isopto(R) Carpine 4%. The mean (SD) Cmax and AUC0-last values on Day were 3.7 (3.2) ng/mL and 7.7 (8.4) ngxhour/mL, respectively. The Tmax values on Day ranged from 0.5 to hour.

PREGNANCY SECTION.

8.1Pregnancy. 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 pregnant woman or can affect reproduction capacity. Isopto(R) Carpine should be given to pregnant woman only if clearly needed.

SPL UNCLASSIFIED SECTION.

1.1Reduction of Elevated Intraocular Pressure (IOP) in Patients With Open-Angle Glaucoma or Ocular Hypertension.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. 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 pregnant woman or can affect reproduction capacity. Isopto(R) Carpine should be given to pregnant woman only if clearly needed.. 8.3Nursing 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 Isopto(R) Carpine is administered to nursing woman.. 8.4Pediatric Use. Safety and effectiveness of pilocarpine hydrochloride ophthalmic solution in pediatric patients have been established.. 8.5Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Poor Illumination: Exercise caution in night driving and other hazardous occupations in poor illumination. (5.1)Preexisting Retinal Disease: Rare cases of retinal detachment have been reported; thorough examination of the retina, including funduscopy is advised in all patients prior to the initiation of therapy. (5.2)Iritis: Caution is advised in patients with iritis. (5.3)Congenital Glaucoma: Caution is advised in pediatric patients with primary congenital glaucoma for control of IOP as cases of paradoxical increase in IOP have been reported. (5.4). Poor Illumination: Exercise caution in night driving and other hazardous occupations in poor illumination. (5.1). Preexisting Retinal Disease: Rare cases of retinal detachment have been reported; thorough examination of the retina, including funduscopy is advised in all patients prior to the initiation of therapy. (5.2). Iritis: Caution is advised in patients with iritis. (5.3). Congenital Glaucoma: Caution is advised in pediatric patients with primary congenital glaucoma for control of IOP as cases of paradoxical increase in IOP have been reported. (5.4). 5.1Poor Illumination. Patients should be advised to exercise caution in night driving and other hazardous occupations in poor illumination. In addition, miotics may cause accommodative spasm. Patients should be advised not to drive or use machinery if vision is not clear.. 5.2Preexisting Retinal Disease. As with all miotics, rare cases of retinal detachment have been reported when used in certain susceptible individuals and those with preexisting retinal disease; therefore, thorough examination of the retina including funduscopy is advised in all patients prior to the initiation of therapy.. 5.3Iritis. Isopto(R) Carpine is not recommended to be used when iritis is present.. 5.4Primary Congenital Glaucoma. Caution is advised when using Isopto(R) Carpine in pediatric patients with primary congenital glaucoma for control of IOP as cases of paradoxical increase in IOP have been reported. In addition, the use of Isopto(R) Carpine is not recommended in pediatric patients diagnosed with glaucoma secondary to anterior segment dysgenesis or uveitis (especially if uveitis is active).. 5.5Contact Lens Wear. Contact lens wearers should be advised to remove their lenses prior to the instillation of Isopto(R) Carpine ophthalmic solution and to wait 10 minutes after dosing before reinserting their contact lenses.