Trial Outcomes & Findings for Sublingual Atropine Bioequivalence by Route of Administration (SABER) (NCT NCT06366087)

NCT ID: NCT06366087

Last Updated: 2026-01-27

Results Overview

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and route using noncompartmental analysis (NCA) methods. AUCinf is summarized by route of administration as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min\*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. Bioequivalence will be considered met if the 90% CI of the ratio for AUCinf lies within 80.00 to 125.00%.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 46 participants
• Primary outcome timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8
• Results posted on: 2026-01-27

Participant Flow

Participants were recruited at a single US site between April 2024 and May 2024. Potential participants signed informed consent before undergoing any screening procedures to confirm eligibility.

Of 107 consented participants, 46 eligible participants were enrolled and randomized to treatment. Of the remaining 61 consented participants, 40 participants did not meet eligibility criteria, and 21 participants were not enrolled or randomized due to enrollment/randomization targets having already been met.

Participant milestones

Measure	Sequence A: Atropine Sulfate Sublingual - Atropine Sulfate Intramuscular Participants dosed sublingually (SL) on Visit 1 (Day 1) and dosed intramuscularly (IM) on Visit 2 (Day 8).	Sequence B: Atropine Sulfate Intramuscular - Atropine Sulfate Sublingual Participants dosed intramuscularly (IM) on Visit 1 (Day 1) and dosed sublingually (SL) on Visit 2 (Day 8).
Overall Study STARTED	23	23
Overall Study COMPLETED	23	22
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Measure	Sequence A: Atropine Sulfate Sublingual - Atropine Sulfate Intramuscular Participants dosed sublingually (SL) on Visit 1 (Day 1) and dosed intramuscularly (IM) on Visit 2 (Day 8).	Sequence B: Atropine Sulfate Intramuscular - Atropine Sulfate Sublingual Participants dosed intramuscularly (IM) on Visit 1 (Day 1) and dosed sublingually (SL) on Visit 2 (Day 8).
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Sublingual Atropine Bioequivalence by Route of Administration (SABER)

Baseline characteristics by cohort

Measure	Sequence A: Atropine Sulfate Sublingual - Atropine Sulfate Intramuscular n=23 Participants Participants dosed sublingually (SL) on Visit 1 (Day 1) and dosed intramuscularly (IM) on Visit 2 (Day 8).	Sequence B: Atropine Sulfate Intramuscular - Atropine Sulfate Sublingual n=23 Participants Participants dosed intramuscularly (IM) on Visit 1 (Day 1) and dosed sublingually (SL) on Visit 2 (Day 8).	Total n=46 Participants Total of all reporting groups
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=25 Participants	2 Participants n=25 Participants	5 Participants n=50 Participants
Age, Continuous	42.4 years STANDARD_DEVIATION 11.64 • n=25 Participants	41.4 years STANDARD_DEVIATION 14.65 • n=25 Participants	41.9 years STANDARD_DEVIATION 13.09 • n=50 Participants
Sex: Female, Male Female	9 Participants n=25 Participants	14 Participants n=25 Participants	23 Participants n=50 Participants
Sex: Female, Male Male	14 Participants n=25 Participants	9 Participants n=25 Participants	23 Participants n=50 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=25 Participants	21 Participants n=25 Participants	41 Participants n=50 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=25 Participants	1 Participants n=25 Participants	2 Participants n=50 Participants
Race (NIH/OMB) Asian	0 Participants n=25 Participants	1 Participants n=25 Participants	1 Participants n=50 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=25 Participants	0 Participants n=25 Participants	1 Participants n=50 Participants
Race (NIH/OMB) Black or African American	10 Participants n=25 Participants	7 Participants n=25 Participants	17 Participants n=50 Participants
Race (NIH/OMB) White	10 Participants n=25 Participants	11 Participants n=25 Participants	21 Participants n=50 Participants
Race (NIH/OMB) More than one race	1 Participants n=25 Participants	3 Participants n=25 Participants	4 Participants n=50 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Region of Enrollment United States	23 participants n=25 Participants	23 participants n=25 Participants	46 participants n=50 Participants

PRIMARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points beyond tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for AUCinf.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and route using noncompartmental analysis (NCA) methods. AUCinf is summarized by route of administration as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. Bioequivalence will be considered met if the 90% CI of the ratio for AUCinf lies within 80.00 to 125.00%.

Outcome measures

Measure	Sublingual n=41 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Bioequivalence of Atropine Sulfate Administered SL Versus Administered IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Infinity (AUCinf).	562.456 min*ng/mL Geometric Coefficient of Variation 23.0	814.860 min*ng/mL Geometric Coefficient of Variation 19.0

PRIMARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and route using noncompartmental analysis (NCA) methods. AUCt is summarized by route of administration as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model. Bioequivalence will be considered met if the 90% CI of the ratio for AUCt lies within 80.00 to 125.00%.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Bioequivalence of Atropine Sulfate Administered SL Versus Administered IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time of Last Quantifiable Data Point (AUCt).	456.944 min*ng/mL Geometric Coefficient of Variation 22.7	683.672 min*ng/mL Geometric Coefficient of Variation 20.5

SECONDARY outcome

Timeframe: 0 hour (pre-dose), 5, 10, 15, 20, 30, and 45 minutes post-dose on Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC45 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC45 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 45 Minutes (AUC45)	11.559 min*ng/mL Geometric Coefficient of Variation 98.9	106.046 min*ng/mL Geometric Coefficient of Variation 34.9

SECONDARY outcome

Timeframe: 0 hour (pre-dose), 5, 10, 15, 20, 30, 45, and 60 minutes post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC60 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC60 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 60 Minutes (AUC60)	21.903 min*ng/mL Geometric Coefficient of Variation 103.1	145.215 min*ng/mL Geometric Coefficient of Variation 31.8

SECONDARY outcome

Timeframe: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, and 90 minutes post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC90 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC90 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 90 (AUC90)	56.521 min*ng/mL Geometric Coefficient of Variation 74.2	217.844 min*ng/mL Geometric Coefficient of Variation 27.8

SECONDARY outcome

Timeframe: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC120 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC120 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 120 Minutes (AUC120)	103.146 min*ng/mL Geometric Coefficient of Variation 52.9	283.847 min*ng/mL Geometric Coefficient of Variation 25.8

SECONDARY outcome

Timeframe: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90, 120, and 150 minutes post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC150 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC150 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 150 Minutes (AUC150)	151.441 min*ng/mL Geometric Coefficient of Variation 41.5	343.066 min*ng/mL Geometric Coefficient of Variation 24.6

SECONDARY outcome

Timeframe: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 240 minutes post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

AUC240 is summarized by route of administration as the geometric mean and coefficient of variation for the geometric mean for all evaluable participants expressed as min*ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
AUC240 - The Relative Bioavailability (Plasma Concentrations) of Atropine Sulfate Administered SL Versus IM as Measured by Area Under the Analyte Concentration Versus Time Curve to Time 240 Minutes (AUC240)	275.948 min*ng/mL Geometric Coefficient of Variation 27.5	484.704 min*ng/mL Geometric Coefficient of Variation 22.7

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

Cmax is summarized by route of administration as the geometric mean and coefficient of variation of the geometric mean for all evaluable participants and expressed as ng/mL. Geometric ratios of least-square means and associated 90% confidence intervals are reported from a linear mixed model.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Maximum Measured Plasma Concentration (Cmax)	1.805 ng/mL Geometric Coefficient of Variation 26.6	3.176 ng/mL Geometric Coefficient of Variation 35.0

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

tmax is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as minutes.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Time to Cmax (Tmax)	118.0 min Standard Deviation 49.19	34.3 min Standard Deviation 22.20

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points beyond tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for t1/2.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

t1/2 is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as minutes.

Outcome measures

Measure	Sublingual n=41 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Apparent Terminal Elimination Half-life (t1/2)	171.089 min Standard Deviation 31.7096	175.682 min Standard Deviation 35.6344

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points beyond tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for λz

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

λz is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as 1/min.

Outcome measures

Measure	Sublingual n=41 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Terminal Elimination Rate Constant (λz)	0.0042 1/min Standard Deviation 0.00077	0.0041 1/min Standard Deviation 0.00082

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points beyond tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for Vd/F.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

Vd/F is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as mL.

Outcome measures

Measure	Sublingual n=41 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Volume of Distribution (Vd/F)	447.17 mL Standard Deviation 119.864	316.62 mL Standard Deviation 88.157

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points beyond tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for CL/F.

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

CL/F is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed as mL/min.

Outcome measures

Measure	Sublingual n=41 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Total Body Clearance (CL/F)	1823.440 mL/min Standard Deviation 420.5016	1248.156 mL/min Standard Deviation 226.2500

SECONDARY outcome

Timeframe: Pre-dose through 8 hours post-dose at Days 1 and 8

Population: PK Analysis Population includes all participants who are randomized, receive at least 1 study drug dose, and have PK samples collected for that period. Participants needed to have plasma concentration results at 3 or more time points from pre-dose through tmax (time to maximum measured plasma concentration) in order to have an evaluable estimate for Ka

Blood samples to measure atropine plasma concentrations were collected during each dosing visit at the following time points: time 0 (predose), and postdose at 5, 10, 15, 20, 30, 45, 60, and 90 minutes, and 2, 2.5, 4, 6, and 8 hours. PK parameters were estimated for each subject and period using noncompartmental analysis (NCA) methods.

Ka is summarized by route of administration as the mean and standard deviation for all evaluable participants and expressed 1/min.

Outcome measures

Measure	Sublingual n=45 Participants Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=44 Participants Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
The Relative Bioavailability of Atropine Sulfate Administered SL Versus IM as Measured by Absorption Rate Constant (Ka)	0.022 1/min Standard Deviation 0.0147	0.117 1/min Standard Deviation 0.2034

Adverse Events

Sublingual

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Intramuscular

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Sublingual n=45 participants at risk Atropine Sulfate Ophthalmic Solution, USP 1% manufactured by Bausch \& Lomb Americas Inc., is a sterile topical anti-muscarinic indicated for mydriasis, cycloplegia, and penalization of the healthy eye to treat amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains the active ingredient atropine sulfate 10 mg, equivalent to 8.3 mg of atropine. Inactive ingredients are boric acid, hydroxypropyl methylcellulose, and water for injection, USP; hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0). Atropine Sulfate Ophthalmic Solution, USP 1% will be supplied in 0.4 mL single-dose vials and will be administered as a single dose to a single participant. 100 μL of Atropine Sulfate Ophthalmic Solution, USP 1% will be given sublingually by pipette to deliver 1.0 mg of atropine sulfate. Before administration, participants will be told to swallow. Once given, participants will be told to try not to swallow for 30 seconds and then swallow normally.	Intramuscular n=46 participants at risk Atropine sulfate injection, USP is a muscarinic antagonist used for temporary blockade of severe/life-threatening muscarinic effects and to treat symptomatic bradycardia. Atropine Sulfate Injection, USP, 8 mg/20 mL (0.4 mg/mL) manufactured by Fresenius Kabi is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; and sodium chloride 9 mg; it may also contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8). Atropine Sulfate Injection, USP will be supplied in 8 mg/20 mL multidose vials (0.4 mg/mL). Each vial will be used to administer multiple doses to multiple participants. 2.5 mL will be injected into the mid-anterolateral thigh to deliver 1.0 mg of atropine sulfate. Vials will be dated/timed and will not be given after 24 hours of first entry.
Cardiac disorders Palpitations	0.00% 0/45 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	2.2% 1/46 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Eye disorders Dry eye	2.2% 1/45 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	0.00% 0/46 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Gastrointestinal disorders Diarrhoea	2.2% 1/45 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	0.00% 0/46 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Gastrointestinal disorders Dry mouth	26.7% 12/45 • Number of events 12 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	47.8% 22/46 • Number of events 22 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Nervous system disorders Headache	2.2% 1/45 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	2.2% 1/46 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.
Nervous system disorders Presyncope	2.2% 1/45 • Number of events 1 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.	0.00% 0/46 • Treatment-emergent adverse events were reported from the time the participant received the first dose of atropine at Day 1 until completion of the follow-up period at Day 15.. Adverse events grade 1 or higher were recorded on the appropriate AE electronic case report form (eCRF) for this study. The study site graded the severity of AEs experienced by the study participants according to the criteria set forth in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.

Additional Information

Michael D. Schwartz, MD MPH/Division of CBRN Countermeasures

BARDA

Phone: (202)-260-0849

Email: Michael.Schwartz@hhs.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place