Prescription Drugs

CLINICAL PHARMACOLOGY 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. 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]. 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. 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.

CLINICAL PHARMACOLOGY Mechanism Of Action Atropine is a reversible antagonist of muscarine-like actions of acetyl-choline and is therefore classified as an antimuscarinic 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. Pharmacodynamics The onset of action after administration of atropine sulfate ophthalmic solution, USP 1%, is usually within 40 minutes with maximal effect being reached in about 2 hours. The effect can last for up to 2 weeks in a normal eye. Pharmacokinetics The bioavailability of atropine sulfate ophthalmic solution, USP 1% was assessed in six healthy subjects, 24 to 29 years of age. Subjects received either 0.3 mg atropine sulfate administered as bolus intravenous injection or 0.3 mg administered as 30 μl instilled unilaterally in the cul-de-sac of the eye. Plasma l-hyoscyamine concentrations were determined over selected intervals up to eight hours after dose administration. The mean bioavailability of topically applied atropine was 63.5 ± 29% (range 19 to 95%) with large inter-individual differences. Mean maximum observed plasma concentration for the ophthalmic solution was 288 ± 73 pg/mL. Maximum concentration was reached in 28 ± 27 min after administration. Terminal half-life of l-hyoscamine was not affected by route of administration and was calculated to be 3 ± 1.2 hours (intravenous) and 2.5 ± 0.8 hours (topical ophthalmic). In another placebo-controlled study, the systemic exposure to l-hyoscyamine, and the anti-cholinergic effects of atropine were investigated in eight ocular surgery patients 56 to 66 years of age, following single topical ocular 0.4 mg atropine dose (given as 40 microliters of atropine sulfate ophthalmic solution, USP 1%). The mean (± standard deviation (SD)) Cmax of l-hyoscyamine in these patients was 860 ± 402 pg/mL, achieved within 8 minutes of eyedrop instillation. Following intravenous administration, the mean (± SD) elimination half-life (t ) of atropine was reported to be longer in pediatric subjects under 2 years (6.9 ± 3.3 hours) and in geriatric patients 65 to 75 years (10.0 ± 7.3 hours), compared to in children over 2 years (2.5 ± 1.2 hours) and in adults 16 to 58 years (3.0 ± 0.9 hours). (see Pediatric Use). Atropine is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, including milk. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. Atropine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic fluid. Atropine binds poorly (about 44%) to plasma protein, mainly to alpha-1 acid glycoprotein; age has no effect on the serum protein binding of atropine. Atropine binding to α-1 acid glycoprotein was concentration dependent (2 to 20 mcg/mL) and nonlinear in vitro and in vivo. There is no gender effect on the pharmacokinetics of atropine administered by injection. Clinical Studies Topical administration of atropine sulfate ophthalmic solution, USP 1% results in cycloplegia and mydriasis which has been demonstrated in several controlled clinical studies in adults and pediatric patients. Maximal mydriasis usually occurs in about 40 minutes and maximal cycloplegia is usually achieved in about 60 to 90 minutes after single administration. Full recovery usually occurs in approximately one week, but may last a couple of weeks.

ISOPTO® ATROPINE (atropine sulfate) Sterile Topical Ophthalmic Solution 1% 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.

Find Lowest Prices on ATROPINE (atropine sulfate) Solution DESCRIPTION Atropine Sulfate Ophthalmic Solution, USP 1% is a sterile topical anticholinergic for ophthalmic use. 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: (C17H23NO3) •H2SO4•H2O Molecular Weight: 694.83 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: benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6. 0), and water for injection USP.

INDICATIONS ISOPTO® Atropine 1% is indicated for: Mydriasis Cycloplegia Penalization Of The healthy Eye In The Treatment Of Amblyopia DOSAGE AND ADMINISTRATION 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. In Individuals 3 Years Of Age Or Greater, Doses May Be Repeated Up To Twice Daily As Needed. HOW SUPPLIED Dosage Forms And Strengths Ophthalmic solution: 1% atropine sulfate (10mg/mL) 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 15 mL filled in 15-mL bottles NDC 0065-0303-15 Storage: Store ISOPTO® Atropine 1% at 2–25°C (36–77°F). Manufactured by: ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA. Revised: December 2016

INDICATIONS Atropine Sulfate Ophthalmic Solution, USP 1% is indicated for: Cycloplegia Mydriasis Penalization Of The Healthy Eye In The Treatment Of Amblyopia DOSAGE AND ADMINISTRATION 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. In individuals 3 years of age or greater, doses may be repeated up to twice daily as needed. HOW SUPPLIED Dosage Forms And Strengths Atropine Sulfate Ophthalmic Solution, USP 1%: each mL contains 10 mg of atropine sulfate equivalent to 8.3 mg of atropine. Storage And Handling Atropine Sulfate Ophthalmic Solution, USP 1% is supplied in a plastic dropper bottle with a red cap in the following sizes: NDC 17478-215-02 2 mL fill in 6cc bottle NDC 17478-215-05 5 mL fill in 6cc bottle NDC 17478-215-15 15 mL fill in 15cc bottle Storage Store at 20° to 25°C (68° to 77°F). Keep tightly closed. Manufactured by: Akorn, Inc. Lake forest, IL 60045. Revised July 2014

PATIENT INFORMATION Advise patients not to touch the dropper tip to any surface as this may contaminate the solution. Advise patients that drops will sting upon instillation and advise patients that they will experience sensitivity to light and blurred vision which may last for a couple of weeks.

OVERDOSE 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. 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.

OVERDOSE 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 adult dose of atropine is not known. In pediatric populations, 10 mg or less may be fatal. CONTRAINDICATIONS Hypersensitivity To Any Component Of This Medication Sections or subsections omitted from the full prescribing information are not listed. 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.

SIDE EFFECTS The following adverse reactions are described below and elsewhere in the labeling: Photophobia and Blurred Vision [see WARNINGS AND PRECAUTIONS] Elevation in Blood Pressure [see WARNINGS AND PRECAUTIONS] Increased Adverse Drug Reaction Susceptibility with Certain Central Nervous System Conditions [see WARNINGS AND PRECAUTIONS] 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. 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. 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. DRUG INTERACTIONS Monoamine Oxidase Inhibitors The use of atropine and monoamine oxidase inhibitors (MAOI) is generally not recommended because of the potential to precipitate hypertensive crisis.

SIDE EFFECTS The following serious adverse reactions are described below and elsewhere in the labeling: Photophobia and Blurred Vision [See WARNINGS AND PRECAUTIONS] Elevation in Blood Pressure [See WARNINGS AND PRECAUTIONS] 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. 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 lid edema may also occur less commonly. 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; restlessness, irritability or delirium from stimulation of the central nervous system; tachycardia; flushed skin of the face and neck. DRUG INTERACTIONS 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.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Photophobia And Blurred Vision Photophobia and blurred vision due to pupil unresponsiveness and cycloplegia may last up to 2 weeks. Elevation Of Blood Pressure Elevation in blood pressure from systemic absorption has been reported following conjunctival instillation of recommended doses of atropine sulfate ophthalmic solution, 1%. Increased Adverse Drug Reaction Susceptibility With Certain Central Nervous System Conditions Individuals with Down syndrome, spastic paralysis, or brain damage are particularly susceptible to central nervous system disturbances, cardiopulmonary, and gastrointestinal toxicity from systemic absorption of atropine. Nonclinical Toxicology 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. Use In Specific Populations 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]. ISOPTO® Atropine 1% should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. 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%. 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. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and adult patients.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Photophobia And Blurred Vision Photophobia and blurred vision due to pupil unresponsiveness and cycloplegia may last up to 2 weeks. Elevation Of Blood Pressure Elevation in blood pressure from systemic absorption has been reported following conjunctival instillation of recommended doses of atropine sulfate ophthalmic solution, USP 1%. Nonclinical Toxicology 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. Use In Specific Populations Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of atropine sulfate in pregnant women. Animal development and reproduction studies have not been conducted with atropine sulfate. Since it is not known whether topically administered atropine sulfate can cause fetal harm, atropine sulfate ophthalmic solution, USP 1% should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Traces of atropine have been found in human milk following administration of atropine solution for injection. Because some systemic absorption occurs from topical administration, caution should be exercised when Atropine Sulfate Ophthalmic Solution, USP 1% is administered to a nursing woman. Pediatric Use Due to the potential for systemic absorption of atropine sulfate ophthalmic solution, 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. Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger adult patients.