Isopto Atropine

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Photophobia and Blurred Vision [see Warnings and Precautions (5.1) ] Elevation in Blood Pressure [see Warnings and Precautions (5.2) ] Increased Adverse Drug Reaction Susceptibility with Certain Central Nervous System Conditions [see Warnings and Precautions (5.3) ] The following adverse reactions have been identified following use of atropine sulfate ophthalmic solution. 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 most common adverse reactions that have been reported are eye pain and stinging on administration, blurred vision, photophobia, superficial keratitis, decreased lacrimation, drowsiness, increased heart rate and blood pressure. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc., at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Ocular Adverse Reactions Eye pain and stinging occurs upon instillation of atropine sulfate ophthalmic solution. Other commonly occurring adverse reactions include blurred vision, photophobia, superficial keratitis and decreased lacrimation. Allergic reactions such as papillary conjunctivitis, contact dermatitis, and eyelid edema may also occur less commonly. 6.2 Systemic Adverse Reactions Systemic effects of atropine are related to its anti-muscarinic activity. Systemic adverse events reported include dryness of skin, mouth, and throat from decreased secretions from mucus membranes; drowsiness; restlessness, irritability or delirium from stimulation of the central nervous system; tachycardia; flushed skin of the face and neck.

4 CONTRAINDICATIONS Atropine sulfate ophthalmic solution should not be used in anyone who has demonstrated a previous hypersensitivity or known allergic reaction to any ingredient of the formulation because it may recur. Hypersensitivity or allergic reaction to any ingredient in the formulation ( 4 )

11 DESCRIPTION ISOPTO® Atropine 1% is a sterile topical ophthalmic solution. Each mL of ISOPTO® Atropine 1% contains 10 mg of atropine sulfate monohydrate equivalent to 9.7 mg/mL of atropine sulfate or 8.3 mg of atropine. Atropine sulfate monohydrate is designated chemically as benzeneacetic acid, α-(hydroxymethyl)-,8-methyl-8-aza-bicyclo-[3.2.1]oct-3-yl ester, endo -( + )-, sulfate(2:1) (salt), monohydrate. Its molecular formula is (C17H23NO3)2 • H2SO4 • H2O and it is represented by the chemical structure: Atropine sulfate monohydrate is colorless crystals or white crystalline powder and has a molecular weight of 694.83. ISOPTO® Atropine 1% has a pH of 3.5 to 6.0. Active ingredient: atropine sulfate monohydrate 1.0% Preservative: benzalkonium chloride 0.01% Inactive ingredients: hypromellose, boric acid, sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water.

2 DOSAGE AND ADMINISTRATION 2.1 In individuals from three (3) months of age or greater, 1 drop topically to the cul-de-sac of the conjunctiva, forty minutes prior to the intended maximal dilation time. 2.2 In individuals 3 years of age or greater, doses may be repeated up to twice daily as needed. In individuals from three (3) months of age or greater 1 drop topically to the cul-de-sac of the conjunctiva, forty minutes prior to the intended maximal dilation time ( 2.1 ) In individuals 3 years of age or greater, doses may be repeated up to twice daily as needed. ( 2.2 )

1 INDICATIONS AND USAGE ISOPTO ® Atropine 1% is indicated for: ISOPTO® Atropine 1% is a muscarinic antagonist indicated for: Mydriasis ( 1.1 ) Cycloplegia ( 1.2 ) Penalization of the healthy eye in the treatment of amblyopia ( 1.3 ) 1.1 Mydriasis 1.2 Cycloplegia 1.3 Penalization of the healthy eye in the treatment of amblyopia

10 OVERDOSAGE In the event of accidental ingestion or toxic overdosage with atropine sulfate ophthalmic solution supportive care may include a short acting barbiturate or diazepam as needed to control marked excitement and convulsions. Large doses for sedation should be avoided because central depressant action may coincide with the depression occurring late in atropine poisoning. Central stimulants are not recommended. Physostigmine, given by slow intravenous injection of 1 to 4 mg (0.5 to 1 mg in pediatric populations), rapidly abolishes delirium and coma caused by large doses of atropine. Since physostigmine is rapidly destroyed, the patient may again lapse into coma after one to two hours, and repeated doses may be required. Artificial respiration with oxygen may be necessary. Cooling measures may be needed to help to reduce fever, especially in pediatric populations. The fatal pediatric and adult doses of atropine are not known.

7 DRUG INTERACTIONS The use of atropine and monoamine oxidase inhibitors (MAOI) is generally not recommended because of the potential to precipitate hypertensive crisis. ( 7 ) 7.1 Monoamine Oxidase Inhibitors The use of atropine and monoamine oxidase inhibitors (MAOI) is generally not recommended because of the potential to precipitate hypertensive crisis.

7.1 Monoamine Oxidase Inhibitors The use of atropine and monoamine oxidase inhibitors (MAOI) is generally not recommended because of the potential to precipitate hypertensive crisis.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atropine acts as a competitive antagonist of the parasympathetic (and sympathetic) acetylcholine muscarinic receptors. Topical atropine on the eye induces mydriasis by inhibiting contraction of the circular pupillary sphincter muscle normally stimulated by acetylcholine. This inhibition allows the countering radial pupillary dilator muscle to contract which results in dilation of the pupil. Additionally, atropine induces cycloplegia by paralysis of the ciliary muscle which controls accommodation while viewing objects. 12.2 Pharmacodynamics The onset of action after administration of ISOPTO Atropine 1% generally occurs in minutes with maximal effect seen in hours and the effect can last multiple days [see Clinical Studies (14) ]. 12.3 Pharmacokinetics In a study of healthy subjects, after topical ocular administration of 30 µL of atropine sulfate ophthalmic solution, 1%, the mean (± SD) systemic bioavailability of l-hyoscyamine was reported to be approximately 64 ± 29% (range 19% to 95%) as compared to intravenous administration of atropine sulfate. The mean (± SD) time to maximum plasma concentration (Tmax) was approximately 28 ± 27 minutes (range 3 to 60 minutes), and the mean (±SD) peak plasma concentration (Cmax) of l-hyoscyamine was 288 ± 73 pg/mL. The mean (±SD) plasma half-life was reported to be approximately 2.5 ± 0.8 hours. In a separate study of patients undergoing ocular surgery, after topical ocular administration of 40 µL of atropine sulfate ophthalmic solution, 1%, the mean (± SD) plasma Cmax of l‑hyoscyamine was 860 ± 402 pg/mL.

12.1 Mechanism of Action Atropine acts as a competitive antagonist of the parasympathetic (and sympathetic) acetylcholine muscarinic receptors. Topical atropine on the eye induces mydriasis by inhibiting contraction of the circular pupillary sphincter muscle normally stimulated by acetylcholine. This inhibition allows the countering radial pupillary dilator muscle to contract which results in dilation of the pupil. Additionally, atropine induces cycloplegia by paralysis of the ciliary muscle which controls accommodation while viewing objects.

12.2 Pharmacodynamics The onset of action after administration of ISOPTO Atropine 1% generally occurs in minutes with maximal effect seen in hours and the effect can last multiple days [see Clinical Studies (14) ].

12.3 Pharmacokinetics In a study of healthy subjects, after topical ocular administration of 30 µL of atropine sulfate ophthalmic solution, 1%, the mean (± SD) systemic bioavailability of l-hyoscyamine was reported to be approximately 64 ± 29% (range 19% to 95%) as compared to intravenous administration of atropine sulfate. The mean (± SD) time to maximum plasma concentration (Tmax) was approximately 28 ± 27 minutes (range 3 to 60 minutes), and the mean (±SD) peak plasma concentration (Cmax) of l-hyoscyamine was 288 ± 73 pg/mL. The mean (±SD) plasma half-life was reported to be approximately 2.5 ± 0.8 hours. In a separate study of patients undergoing ocular surgery, after topical ocular administration of 40 µL of atropine sulfate ophthalmic solution, 1%, the mean (± SD) plasma Cmax of l‑hyoscyamine was 860 ± 402 pg/mL.

20221007

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3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution: 1% atropine sulfate (10mg/mL) Ophthalmic solution: 1% atropine sulfate (10mg/mL) ( 3 )

Isopto Atropine atropine sulfate Atropine Sulfate Atropine Benzalkonium Chloride Hypromelloses Boric Acid Sodium Hydroxide Hydrochloric Acid Water Chemical Structure 5 mL Carton 5 mL Label

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Atropine sulfate was negative in the Salmonella/microsome mutagenicity test. Studies to evaluate carcinogenicity and impairment of fertility have not been conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Atropine sulfate was negative in the Salmonella/microsome mutagenicity test. Studies to evaluate carcinogenicity and impairment of fertility have not been conducted.

NDA208151

Isopto Atropine

atropine sulfate

0065-0303

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 0065-0303-55 Alcon ® Isopto ® Atropine (atropine sulfate ophthalmic solution) 1% 5 mL Sterile USUAL ADULT DOSAGE: One drop topically in the eye(s) up to twice daily. For other dosage information, read enclosed insert. PRECAUTION: Do not touch dropper tip to any surface, as this may contaminate the solution. STORAGE: Store at 2°-25°C (36°-77°F). Read enclosed insert. Rx Only INGREDIENTS: Each mL contains: Active: atropine sulfate monohydrate 1.0%. Preservative: benzalkonium chloride 0.01%. Inactives: hypromellose 0.5%, boric acid, sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water. © 2003, 2018 Novartis Alcon ® ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA Product of Germany 9016388-0618 SN: LOT: EXP.: GTIN: 00300650303552 NDC 0065-0303-55 Alcon ® Isopto ® Atropine (atropine sulfate ophthalmic solution) 1% Sterile 5mL Rx Only INGREDIENTS: Each mL contains: Active: atropine sulfate monohydrate 1.0%. Preservative: benzalkonium chloride 0.01%. Inactives: hypromellose 0.5%, boric acid, sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water. PRECAUTION: Do not touch dropper tip to any surface, as this may contaminate the solution. USUAL ADULT DOSAGE: One drop topically in the eye(s) up to twice daily. For other dosage information, read enclosed insert. FOR TOPICAL OPHTHALMIC USE. STORAGE: Store at 2°-25°C (36°-77°F). ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA ©2018 Novartis H15250-0318

17 PATIENT COUNSELING INFORMATION Advise patients not to drive or engage in other hazardous activities while pupils are dilated. Advise patient that they may experience blurry vision and sensitivity to light and should protect their eyes in bright illumination during dilation. These effects may last up to a couple weeks. Advise patients that they may experience drowsiness. Advise patients not to touch the dispenser tip to any surface, as this may contaminate the solution. ALCON ® A Novartis company Fort Worth, Texas 76134 USA © 2016, 2018 Novartis

14 CLINICAL STUDIES Topical administration of ISOPTO® Atropine 1% results in mydriasis and/or cycloplegia, with efficacy demonstrated in both adults and children. The maximum effect for mydriasis is achieved in about 30–40 minutes after administration, with recovery after approximately 7–10 days. The maximum effect for cycloplegia is achieved within 60–180 minutes after administration, with recovery after approximately 7–12 days.

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

8.4 Pediatric Use Due to the potential for systemic absorption of atropine sulfate ophthalmic solution the use of ISOPTO® Atropine 1% in children under the age of 3 months is not recommended and the use in children under 3 years of age should be limited to no more than one drop per eye per day. Safety and efficacy in children above the age of 3 months has been established in adequate and well controlled trials.

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with ISOPTO® Atropine 1% administration in pregnant women to inform a drug-associated risk. Adequate animal development and reproduction studies have not been conducted with atropine sulfate. In humans, 1% atropine sulfate is systemically bioavailable following topical ocular administration [see Clinical Pharmacology (12.3) ] . ISOPTO® Atropine 1% should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with ISOPTO® Atropine 1% administration in pregnant women to inform a drug-associated risk. Adequate animal development and reproduction studies have not been conducted with atropine sulfate. In humans, 1% atropine sulfate is systemically bioavailable following topical ocular administration [see Clinical Pharmacology (12.3) ] . ISOPTO® Atropine 1% should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 8.2 Lactation There is no information to inform risk regarding the presence of atropine in human milk following ocular administration of ISOPTO® Atropine 1% to the mother. The effects on breastfed infants and the effects on milk production are also unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ISOPTO® Atropine 1% and any potential adverse effects on the breastfed child from ISOPTO® Atropine 1%. 8.4 Pediatric Use Due to the potential for systemic absorption of atropine sulfate ophthalmic solution the use of ISOPTO® Atropine 1% in children under the age of 3 months is not recommended and the use in children under 3 years of age should be limited to no more than one drop per eye per day. Safety and efficacy in children above the age of 3 months has been established in adequate and well controlled trials. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING ISOPTO® Atropine 1% is supplied sterile in low-density polyethylene plastic DROP-TAINER® dispensers with low-density polyethylene tips and red polypropylene caps as follows: 5 mL filled in 8-mL bottles NDC 0065-0303-55 Storage: Store ISOPTO® Atropine 1% at 2–25°C (36–77°F).