DARTISLA ODT

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: Precipitation of Acute Glaucoma [see Warnings and Precautions ( 5.1 )] Partial or Complete Mechanical Intestinal Obstruction [see Warnings and Precautions ( 5.2 )] Gastrointestinal Adverse Reactions due to Decreased Gastrointestinal Motility [see Warnings and Precautions ( 5.3 )] Cognitive and Visual Adverse Reactions [see Warnings and Precautions ( 5.4 )] Heat Prostration at High Environmental Temperatures [see Warnings and Precautions ( 5.5 )] Other Conditions Exacerbated by Anticholinergic Adverse Reactions [see Warnings and Precautions ( 5.6 )] Increased Risk of Anticholinergic Adverse Reactions in Geriatric Patients [see Warnings and Precautions ( 5.7 )] The following adverse reactions associated with the use of glycopyrrolate, or other anticholinergic drugs, were identified in clinical studies or postmarketing reports. Because some of 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. Cardiac Disorders: chest, pain, hypertension, tachycardia Endocrine Disorders: decreased sweating Eye Disorders: blurred vision, cycloplegia, dilatation of the pupil, increased ocular tension Gastrointestinal Disorders: bloated feeling, constipation, dry mouth, dysgeusia, nausea, vomiting Immune System Disorders : anaphylaxis [see Contraindications ( 4 )] Nervous System Disorders : agitation, dizziness, drowsiness, headache, insomnia, mental confusion, nervousness, weakness Respiratory Disorders: respiratory depression, throat irritation Renal and Urinary Disorders: urinary hesitancy, urinary retention Reproductive System and Breast Disorders: impotence, suppression of lactation Vascular Disorders: flushing Adverse reactions include blurred vision, drowsiness, decreased sweating, flushing, vomiting, constipation, dry mouth, tachycardia, and urinary retention. To report SUSPECTED ADVERSE REACTIONS, contact Edenbridge Pharmaceuticals, LLC at 1-877-381-3336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS DARTISLA ODT is contraindicated in: Patients at risk for anticholinergic toxicity due to an underlying medical condition, including: Glaucoma [see Warnings and Precautions ( 5.1 )] Obstructive uropathies including prostatic hypertrophy Mechanical obstructive diseases of gastrointestinal tract (e.g., pyloroduodenal stenosis, strictures) [see Warnings and Precautions ( 5.2 )] Gastrointestinal motility disorders (e.g., achalasia, paralytic ileus, intestinal atony) [see Warnings and Precautions ( 5.3 )] Bleeding gastrointestinal ulcer Active inflammatory or infectious colitis which can lead to toxic megacolon History of or current toxic megacolon Myasthenia gravis Patients with a hypersensitivity to glycopyrrolate or any of the inactive ingredients in DARTISLA ODT [see Adverse Reactions ( 6 ) and Description ( 11 )] . Patients at risk for anticholinergic toxicity due to various underlying medical conditions ( 4 , 5.1 , 5.2 , 5.3 ) Hypersensitivity to glycopyrrolate or the inactive ingredients ( 4 )

11 DESCRIPTION DARTISLA ODT (glycopyrrolate) orally disintegrating tablets contains the synthetic anticholinergic, glycopyrrolate. Glycopyrrolate is a quaternary ammonium compound with the following chemical name: 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide. The empirical formula for glycopyrrolate is C 19 H 28 BrNO 3 , the molecular weight is 398.3 g/mol, and the structural formula is: Each DARTISLA ODT contains: glycopyrrolate, USP 0.85 mg or 1.7 mg as the active ingredient. The inactive ingredients include black cherry, citric acid, fish gelatin (high molecular weight), mannitol, poloxamer 188, purified water and sucralose micronized. structure

2 DOSAGE & ADMINISTRATION Important Dosing Information ( 2.1 ) Patients receiving another oral tablet dosage form of glycopyrrolate may be switched as follows:. 1 mg dosage strength to DARTISLA ODT 0.85 mg. 2 mg dosage strength to DARTISLA ODT 1.7 mg Recommended Dosage Initial Dosage : 0.85 mg three times daily (in the morning, early afternoon, and at bedtime) at leasy one hour before or two hours after food. ( 2.2 , 2.3 ) May require 1.7 mg at bedtime for overnight control of symptoms. ( 2.2 ) For maintenance, 0.85 mg twice a day is frequently adequate. ( 2.2 ) Dosage for patients switching from 2 mg glycopyrrolate products : 1.7 mg two or three times daily at equally spaced intervals. ( 2.2 ) Maximum recommended daily dosage is 6.8 mg. ( 2.2 ) Use the lowest effective dosage to control symptoms. ( 2.2 ) 2.1 Important Dosing Information Patients receiving the 1 mg dosage strength of another oral tablet dosage form of glycopyrrolate may be switched to the 0.85 mg dosage strength of DARTISLA ODT [see Dosage Forms and Strengths ( 3 ) and Clinical Pharmacology ( 12.3 )]. Patients receiving the 2 mg dosage strength of another oral tablet dosage form of glycopyrrolate may be switched to the 1.7 mg dosage strength of DARTISLA ODT [see Dosage Forms and Strengths ( 3 ) and Clinical Pharmacology ( 12.3 ) ]. 2.2 Recommended Dosage Initial dosage: • The recommended initial dosage is 0.85 mg orally three times daily (in the morning, early afternoon, and at bedtime). • Some patients may require 1.7 mg at bedtime to assure overnight control of symptoms. • For maintenance, a dosage of 0.85 mg orally twice is frequently adequate. Dosage for patients switching from 2 mg glycopyrrolate products: • The recommended dosage is 1.7 mg two or three times daily at equally spaced intervals. • The maximum recommended daily dosage is 6.8 mg. • Use the lowest effective dosage to control symptoms. 2.3 Administration Instructions Administer DARTISLA ODT at least one hour before or two hours after food [see Clinical Pharmacology ( 12.3 )] . Use dry hands when opening the blister card and do not open the blister until ready to administer. Open the package and peel back the foil on the blister to expose the tablet and gently remove from the blister. Do not push the tablet through the foil. Do not break or cut the tablet. Immediately place the tablet on the tongue, allow it to disintegrate, and swallow without water.

1 INDICATIONS & USAGE DARTISLA ODT is indicated in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer. Limitations of Use DARTISLA ODT is not indicated as monotherapy for treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established. DARTISLA ODT is an anticholinergic indicated in adults to reduce symptoms of a peptic ulcer as an adjunct to treatment of peptic ulcer. Limitations of Use: Not indicated as monotherapy for treatment of peptic ulcer because effectiveness in peptic ulcer healing has not been established.

9.1 Controlled Substance

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance

10 OVERDOSAGE Signs and symptoms of glycopyrrolate overdosage are related to excessive anti-muscarinic anticholinergic activity and are generally peripheral (e.g., flushing, hyperthermia, tachycardia, ileus, urinary retention, loss of ocular accommodation and light sensitivity due to mydriasis), but central nervous system toxicity (agitation, seizures, hyperthermia) may also occur. If over-exposure occurs, call the Poison Control Center at 1-800-222-1222 for current information on the management of glycopyrrolate poisoning and overdosage. Management of glycopyrrolate overdosage is based upon presenting signs and symptoms, including close observation for severe or life-threatening complications which may require respiratory and cardiovascular monitoring and support. Consider administration of activated charcoal and/or use of a reversible anticholinesterase as appropriate or recommended by Poison Control.

7 DRUG INTERACTIONS Concomitant use is not recommended with: Other Anticholinergic Drugs ( 5.3 , 5.4 , 5.6 , 7.1 ) Drugs with Altered Absorption due to Decreased GI Motility ( 7.2 ) GI Toxicity with Solid Oral Dosage Forms of Potassium Chloride. ( 7.3 ) 7.1 Other Anticholinergic Drugs There is potential for an additive interaction between glycopyrrolate and concomitantly used anticholinergic drugs (e.g., tricyclic antidepressants, anti-epileptics, class I antiarrhythmics, anti-spasmodics, amantadine) resulting in increased anticholinergic adverse reactions. Coadministration of antipsychotics with glycopyrrolate may lead to worsening of tardive dyskinesia. DARTISLA ODT is not recommended in patients taking other anticholinergic drugs [see Warnings and Precautions ( 5.3 , 5.4 , 5.6 )] . 7.2 Drugs with Altered Absorption due to Decreased Gastrointestinal Motility and Increased Transit Time Decreased gastrointestinal motility by glycopyrrolate may impact absorption of other drugs leading to increased or decreased drug exposure. DARTISLA ODT is not recommended in patients taking other drugs that are affected by altered gastrointestinal motility. [see Warnings and Precautions ( 5.3 ) ] . 7.3 Gastrointestinal Toxicity with Solid Oral Dosage Forms of Potassium Chloride Oral glycopyrrolate may worsen gastrointestinal mucosal injury reported with solid oral dosage forms of potassium chloride due to decreased gastric motility and increased transit time leading to prolonged contact with the gastrointestinal mucosa. DARTISLA ODT is not recommended in patients taking solid oral dosage forms of potassium chloride.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Glycopyrrolate, an anticholinergic (antimuscarinic) agent, inhibits the action of acetylcholine on parietal cells in the stomach and decreases the volume and acidity of gastric secretions. 12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with DARTISLA ODT. 12.3 Pharmacokinetics Absorption After DARTISLA ODT administration under fasted conditions, the mean (SD) C max was 390 (±237) pg/mL, and the mean AUC 0-t and AUC 0-inf was 1862 (±1116) and 1977 (± 1171) pg·hr/mL, respectively. The median time to maximum plasma concentration was 3 hours. After DARTISLA ODT 1.7 mg administration, the C max and AUC of glycopyrrolate were comparable to an oral 2 mg glycopyrrolate tablet [see Dosage and Administration ( 2.2 )] . When DARTISLA ODT was placed in the mouth and immediately swallowed with 240 mL water, the mean C max and AUC of glycopyrrolate decreased by 24% and 20%, respectively, compared to administration without water [see Dosage and Administration ( 2.2 ) ] . Effect of Food In healthy adults, a high-fat, high-calorie meal (939 calories, 60% fat) significantly reduced the absorption of glycopyrrolate following administration of DARTISLA ODT 1.7 mg. The mean C max and AUC were approximately 83% and 77% lower, respectively, than those observed under fasted conditions [see Dosage and Administration ( 2.2 )] . Elimination After DARTISLA ODT 1.7 mg administration, the mean plasma half-life was 2.8 hours. Specific Populations Patients with Renal Impairment In published literature, glycopyrrolate 4 mcg/kg was administered intravenously (DARTISLA ODT is not recommended for intravenous use) in uremic patients undergoing renal transplantation surgery. The mean AUC (10.6 mcg·h/L), and 24-hour urinary excretion (7%) for glycopyrrolate were significantly different from normal healthy adult subjects undergoing general surgery (3.7 mcg·h/L, and 65%, respectively) [see Use in Specific Populations ( 8.6 )] .

12.1 Mechanism of Action Glycopyrrolate, an anticholinergic (antimuscarinic) agent, inhibits the action of acetylcholine on parietal cells in the stomach and decreases the volume and acidity of gastric secretions.

12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with DARTISLA ODT.

12.3 Pharmacokinetics Absorption After DARTISLA ODT administration under fasted conditions, the mean (SD) C max was 390 (±237) pg/mL, and the mean AUC 0-t and AUC 0-inf was 1862 (±1116) and 1977 (± 1171) pg·hr/mL, respectively. The median time to maximum plasma concentration was 3 hours. After DARTISLA ODT 1.7 mg administration, the C max and AUC of glycopyrrolate were comparable to an oral 2 mg glycopyrrolate tablet [see Dosage and Administration ( 2.2 )] . When DARTISLA ODT was placed in the mouth and immediately swallowed with 240 mL water, the mean C max and AUC of glycopyrrolate decreased by 24% and 20%, respectively, compared to administration without water [see Dosage and Administration ( 2.2 ) ] . Effect of Food In healthy adults, a high-fat, high-calorie meal (939 calories, 60% fat) significantly reduced the absorption of glycopyrrolate following administration of DARTISLA ODT 1.7 mg. The mean C max and AUC were approximately 83% and 77% lower, respectively, than those observed under fasted conditions [see Dosage and Administration ( 2.2 )] . Elimination After DARTISLA ODT 1.7 mg administration, the mean plasma half-life was 2.8 hours. Specific Populations Patients with Renal Impairment In published literature, glycopyrrolate 4 mcg/kg was administered intravenously (DARTISLA ODT is not recommended for intravenous use) in uremic patients undergoing renal transplantation surgery. The mean AUC (10.6 mcg·h/L), and 24-hour urinary excretion (7%) for glycopyrrolate were significantly different from normal healthy adult subjects undergoing general surgery (3.7 mcg·h/L, and 65%, respectively) [see Use in Specific Populations ( 8.6 )] .

20231019

5

3 DOSAGE FORMS & STRENGTHS Dartisla ODT is available as: · 0.85 mg of glycopyrrolate Orally Disintegrating Tablets (white to off-white, round, and debossed with the symbol ) · 1.7 mg of glycopyrrolate Orally Disintegrating Tablets (white to off-white, round, and debossed with the symbol ) Orally Disintegrating Tablets: 0.85 mg and 1.7 mg ( 3 ) 0.85-debossing 1.7-debossing

DARTISLA ODT Glycopyrrolate Orally Disintegrating Tablets GLYCOPYRROLATE Glycopyrronium Double;bridge DARTISLA ODT Glycopyrrolate Orally Disintegrating Tablets GLYCOPYRROLATE Glycopyrronium Single;bridge

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Reproduction studies in rats resulted in diminished rates of conception, in a dose-related manner. Studies in dogs suggest that diminished rates of conception may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Reproduction studies in rats resulted in diminished rates of conception, in a dose-related manner. Studies in dogs suggest that diminished rates of conception may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate.

NDA215019

DARTISLA ODT

Glycopyrrolate Orally Disintegrating Tablets

82111-517

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL blister-label carton-label 0.85mg-blister 0.85-carton

Dosage and Administration Important Dosing information 09/2023 Recommended Dosage 09/2023

17 PATIENT COUNSELING INFORMATION Precipitation of Acute Glaucoma Advise patient to discontinue DARTISLA ODT and promptly seek medical care if they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes accompanied by dilated pupils) [see Warnings and Precautions ( 5.1 )] . Partial or Complete Mechanical Intestinal Obstruction Advise patients to contact their healthcare provider if diarrhea occurs, especially in patients with ileostomy or colostomy [see Warnings and Precautions ( 5.2 )] . Gastrointestinal Adverse Reactions Due to Decreased Gastrointestinal Motility Inform patients that DARTISLA ODT may cause adverse reactions related to decreased gastrointestinal motility and to report to their healthcare provider if they experience symptoms such as vomiting, early satiety, abdominal distention, and constipation [see Warnings and Precautions ( 5.3 )] . Cognitive and Visual Adverse Reactions Inform patients that DARTISLA ODT may cause cognitive or visual impairment and not to operate motor vehicles or other dangerous machinery or perform other hazardous tasks until they are reasonably certain that DARTISLA ODT does not affect them adversely. Advise patients to discontinue DARTISLA ODT immediately and contact their healthcare provider if symptoms develop (e.g., drowsiness or blurred vision) [see Warnings and Precautions ( 5.4 )] . Heat Prostration at High Environmental Temperatures Inform patients that DARTISLA ODT can reduce sweating, leading to the possibility of heat exhaustion or heat stroke. Advise patients to avoid exposure to hot or very warm environmental temperatures [see Warnings and Precautions ( 5.5 )] . Dosage and Administration Instructions Administer DARTISLA ODT at least one hour before or two hours after food [see Dosage and Administration ( 2.2 )] . Use dry hands when handling the blister card and do not open the blister until ready to administer. Open the package and peel back the foil on the blister to expose the tablet and gently remove from the blister. Do not push the tablet through the foil. Do not break or cut the tablet. Immediately place the tablet on the tongue, allow it to disintegrate, and swallow without water [see Dosage and Administration ( 2.3 )] . Manufactured by: Catalent Pharma Solutions Limited Frankland Road Blagrove, Swindon Wiltshire SN5 8RU, United Kingdom (GBR) Manufactured for: Edenbridge Pharmaceuticals, LLC Parsippany, NJ 07054 © 2023 Edenbridge Pharmaceuticals, LLC eb-pic

8.5 Geriatric Use Geriatric patients 65 years of age and older may be more sensitive to the anticholinergic adverse reactions of glycopyrrolate leading to complications of urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures; therefore, DARTISLA ODT is not recommended in geriatric patients and may be contraindicated in some geriatric patients with underlying medical conditions [see Contraindications ( 4 ) and Warnings and Precautions ( 5 )] .

8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergic drugs, glycopyrrolate may cause suppression of lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DARTISLA ODT and any potential adverse effects on the breastfed infant from DARTISLA ODT.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Over decades of use, there is an absence of published data on orally administered glycopyrrolate in pregnant women, including an absence of any reports of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, at non-maternally toxic doses of oral glycopyrrolate, there were no adverse developmental effects in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean body weight that recovered post nursing, with no other developmental effects observed (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data At non-maternally toxic doses of oral glycopyrrolate there were no effects on embryo-fetal development or toxicity in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean body weight that recovered post nursing, with no other developmental effects observed. In a published reproductive and developmental study, male and female rats were administered glycopyrrolate in the diet at 0, 32.5, 63 and 130 mg/kg/day for 3 to 5 weeks and through up to three consecutive litters. There was no indication of abnormalities in the pups of treated dams. There was a decreased rate of conception and in survival rate at weaning for all treated animals in a dose-related manner. Diminished rates of conception may be due to diminished seminal secretion [see Nonclinical Toxicology ( 13.1 )] .

8 USE IN SPECIFIC POPULATIONS Ren al Impairment: Discontinue if anticholinergic adverse reactions. ( 8.6 ) 8.1 Pregnancy Risk Summary Over decades of use, there is an absence of published data on orally administered glycopyrrolate in pregnant women, including an absence of any reports of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, at non-maternally toxic doses of oral glycopyrrolate, there were no adverse developmental effects in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean body weight that recovered post nursing, with no other developmental effects observed (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data At non-maternally toxic doses of oral glycopyrrolate there were no effects on embryo-fetal development or toxicity in rats or rabbits. A pre- and post-natal development study of oral glycopyrrolate in rats showed a decrease in pup mean body weight that recovered post nursing, with no other developmental effects observed. In a published reproductive and developmental study, male and female rats were administered glycopyrrolate in the diet at 0, 32.5, 63 and 130 mg/kg/day for 3 to 5 weeks and through up to three consecutive litters. There was no indication of abnormalities in the pups of treated dams. There was a decreased rate of conception and in survival rate at weaning for all treated animals in a dose-related manner. Diminished rates of conception may be due to diminished seminal secretion [see Nonclinical Toxicology ( 13.1 )] . 8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergic drugs, glycopyrrolate may cause suppression of lactation. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DARTISLA ODT and any potential adverse effects on the breastfed infant from DARTISLA ODT. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Geriatric patients 65 years of age and older may be more sensitive to the anticholinergic adverse reactions of glycopyrrolate leading to complications of urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures; therefore, DARTISLA ODT is not recommended in geriatric patients and may be contraindicated in some geriatric patients with underlying medical conditions [see Contraindications ( 4 ) and Warnings and Precautions ( 5 )] . 8.6 Renal Impairment Glycopyrrolate is substantially excreted by the kidney [see Clinical Pharmacology ( 12.3 )] . Monitor patients with renal impairment for anticholinergic adverse reactions [see Adverse Reactions ( 6 )] . If anticholinergic adverse reactions occur, discontinue DARTISLA ODT.

16 HOW SUPPLIED/STORAGE AND HANDLING DARTISLA ODT is supplied as: 0.85 mg glycopyrrolate as a white to off-white, round orally disintegrating tablet debossed with the symbol . Available as: NDC 82111-517-01: 30 orally disintegrating tablets per carton. Each carton has 3 blister cards containing 10 orally disintegrating tablets each. 1.7 mg glycopyrrolate as a white to off-white, round orally disintegrating tablets debossed with the symbol . Available as: NDC 82111-518-01: 30 orally disintegrating tablets per carton. Each carton has 3 blister cards containing 10 orally disintegrating tablets each. Store at 20°C to 25°C (68°F to 77°F); with excursions between 15°C to 30°C (59°F to 86°F) [USP controlled room temperature]. 0.85 1.7-debossing