Atropine Sulfate

6 ADVERSE REACTIONS The following serious 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) ] 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. 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 Bausch & Lomb Incorporated at 1-800-553-5340 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 mucous 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, USP 1% 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 Atropine Sulfate Ophthalmic Solution, USP 1% is an aseptically prepared, sterile solution for topical ophthalmic use. The product does not contain an antimicrobial preservative. The active ingredient is represented by the chemical structure: Chemical Name: Benzeneacetic acid, α-(hydroxymethyl)-, 8-methyl-8-azabicyclo[3.2.1.]oct-3-yl ester, endo –(±)-, sulfate (2:1) (salt), monohydrate. Molecular Formula: (C 17 H 23 NO 3 ) 2 • H 2 SO 4 • H 2 O Molecular Weight: 694.84 g/mol Each mL of Atropine Sulfate Ophthalmic Solution, USP 1% contains: Active: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactives: boric acid, hydroxypropyl methylcellulose, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection USP. chemstructure

2 DOSAGE AND ADMINISTRATION In individuals from three (3) months of age or greater, 1 drop topically to the cul-de-sac of the conjunctiva in one or both eyes as indicated, forty minutes prior to the intended maximal dilation time. In individuals 3 years of age or greater, doses may be repeated up to twice daily as needed. Discard the single-dose vial immediately after use in one or both eyes. • 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 Atropine Sulfate Ophthalmic Solution, USP 1% is indicated for: Atropine is an anti-muscarinic agent 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, USP 1%, 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 adult dose of atropine is not known. In pediatric populations, 10 mg or less may be fatal.

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 (MAOI) 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 is a reversible antagonist of muscarine-like actions of acetylcholine and is therefore classified as an anti-muscarinic agent. Atropine is relatively selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at non-muscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors. The pupillary constrictor muscle depends on muscarinic cholinoceptor activation. This activation is blocked by topical atropine resulting in unopposed sympathetic dilator activity and mydriasis. Atropine also weakens the contraction of the ciliary muscle, or cycloplegia. Cycloplegia results in loss of the ability to accommodate such that the eye cannot focus for near vision. 12.2 Pharmacodynamics The onset of action after administration of Atropine Sulfate Ophthalmic Solution, USP 1% generally occurs within 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 median (range) time to maximum plasma concentration (Tmax) was 19 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, which was observed within 8 minutes following administration.

12.1 Mechanism of Action Atropine is a reversible antagonist of muscarine-like actions of acetylcholine and is therefore classified as an anti-muscarinic agent. Atropine is relatively selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at non-muscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1, M2, and M3 subgroups of muscarinic receptors. The pupillary constrictor muscle depends on muscarinic cholinoceptor activation. This activation is blocked by topical atropine resulting in unopposed sympathetic dilator activity and mydriasis. Atropine also weakens the contraction of the ciliary muscle, or cycloplegia. Cycloplegia results in loss of the ability to accommodate such that the eye cannot focus for near vision.

12.2 Pharmacodynamics The onset of action after administration of Atropine Sulfate Ophthalmic Solution, USP 1% generally occurs within 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 median (range) time to maximum plasma concentration (Tmax) was 19 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, which was observed within 8 minutes following administration.

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3 DOSAGE FORMS AND STRENGTHS Atropine Sulfate Ophthalmic Solution, USP 1%: each mL contains 10 mg of atropine sulfate. Ophthalmic solution: 1% atropine sulfate (10 mg/mL) ( 3 ).

Atropine Sulfate Atropine Sulfate ATROPINE SULFATE ATROPINE BORIC ACID HYDROCHLORIC ACID SODIUM HYDROXIDE WATER HYPROMELLOSE, UNSPECIFIED

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.

NDA213581

Atropine Sulfate

Atropine Sulfate

24208-965

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

Package/Label Display Panel NDC 24208-965-01 Atropine Sulfate Ophthalmic Solution, USP 1% Sterile FOR TOPICAL OPHTHALMIC USE NOT FOR INJECTION Rx only 10 x 0.4 mL Single-Dose Vials BAUSCH + LOMB 9769500 carton

17 PATIENT COUNSELING INFORMATION • Advise patients that drops will sting upon instillation 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 to keep the single-dose vials in the foil pouches until ready to use. The solution from one single-dose vial is to be used immediately after opening to dose one or both eye(s) of a single patient. The single-dose vial, including any remaining contents, should be discarded immediately after administration [see Dosage and Administration (2) ] . • Advise patients not to touch the tip of the single-dose vial to their eye or to any surface, in order to avoid eye injury or contamination of the solution. Distributed by: Bausch & Lomb Americas Inc. Bridgewater, NJ 08807 USA © 2022 Bausch & Lomb Incorporated or its affiliates 9775700

14 CLINICAL STUDIES Topical administration of Atropine Sulfate Ophthalmic Solution, USP 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 and effectiveness have been observed between elderly and younger adult patients.

8.4 Pediatric Use Due to the potential for systemic absorption, the use of Atropine Sulfate Ophthalmic Solution, USP 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 of Atropine Sulfate Ophthalmic Solution, USP 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) ] . Atropine Sulfate Ophthalmic Solution, USP 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 of Atropine Sulfate Ophthalmic Solution, USP 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) ] . Atropine Sulfate Ophthalmic Solution, USP 1% should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 8.2 Lactation Risk Summary There is no information to inform risk regarding the presence of atropine in human milk following ocular administrations of Atropine Sulfate Ophthalmic Solution, USP 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 Atropine Sulfate Ophthalmic Solution, USP 1% and any potential adverse effects on the breastfed child from Atropine Sulfate Ophthalmic Solution, USP 1%. 8.4 Pediatric Use Due to the potential for systemic absorption, the use of Atropine Sulfate Ophthalmic Solution, USP 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 and effectiveness have been observed between elderly and younger adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Atropine Sulfate Ophthalmic Solution, USP 1% is supplied as an aseptically prepared, sterile solution for topical ophthalmic use supplied as a 0.4 mL fill in a translucent, low-density polyethylene, single-dose vial. One (1) strip of 5 single-dose vials is packaged into a foil pouch. NDC 24208-965-01 10 single-dose vials. 2 foil pouches each containing one strip of 5 single-dose vials. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F). Store single-dose vials in the foil pouches. Opened vials cannot be resealed and should be discarded immediately after use.