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.

5.1 Precipitation of Acute Glaucoma

Glycopyrrolate may cause increased intraocular pressure in patients with glaucoma and reduce the effects of antiglaucoma agents. Instruct patients 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 Contraindications (4)]

5.2 Partial or Complete Mechanical Intestinal Obstruction

DARTISLA ODT may worsen intestinal mechanical obstruction, and diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. If partial or complete intestinal obstruction is suspected, discontinue use of DARTISLA ODT and evaluate for potential intestinal obstruction [see Contraindications (4)].

5.3 Gastrointestinal Adverse Reactions Due to Decreased Gastrointestinal Motility

Glycopyrrolate reduces gastrointestinal motility and may result in delayed gastric emptying, constipation, and intestinal pseudo-obstruction and may precipitate or aggravate paralytic ileus and toxic megacolon [see Contraindications (4)]. The risk of gastrointestinal adverse reactions is further increased with use of other anticholinergics and other medications that decrease gastrointestinal peristalsis. Monitor patients for symptoms of decreased gastrointestinal motility. Concomitant use of DARTISLA ODT and other anticholinergics or other medications that decrease GI peristalsis is not recommended [see Drug Interactions (7.2)].

5.4 Cognitive and Visual Adverse Reactions

Glycopyrrolate may produce drowsiness and blurred vision and impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle, operating machinery or performing other hazardous work [see Adverse Reactions (6)]. Concomitant use of other drugs that have anticholinergic properties may increase these effects [see Drug Interactions (7.1)]. Inform patients 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. Discontinue DARTISLA ODT if signs or symptoms of cognitive or visual impairment develop.

5.5 Heat Prostration at High Environmental Temperatures

In the presence of a high environmental temperature, heat prostration resulting in fever and heat stroke can occur with use of DARTISLA ODT due to decreased sweating, particularly in geriatric patients [see Adverse Reactions (6)]. Advise patients to avoid exposure to hot or very warm environmental temperatures when taking DARTISLA ODT. DARTISLA ODT is not recommended in geriatric patients [see Warnings and Precautions (5.7)].

5.6 Other Conditions Exacerbated by Anticholinergic Adverse Reactions

DARTISLA ODT is not recommended in patients with other conditions exacerbated by anticholinergic adverse reactions (e.g., autonomic neuropathy, hyperthyroidism, cardiac disease, and hiatal hernia associated with reflux esophagitis) and in patients taking other anticholinergic medications [see Drug Interactions (7.1)].

5.7 Increased Risk of Anticholinergic Adverse Reactions in Geriatric Patients

Geriatric patients 65 years of age and older are at increased risk of anticholinergic adverse reactions that may lead to complications of urinary retention, bowel obstruction, heat prostration, arrhythmias, delirium, and falls or fractures. DARTISLA ODT is not recommended in geriatric patients and may be contraindicated in some geriatric patients with underlying medical conditions  [see Contraindications (4), Warnings and Precautions (5.2, 5.5), Adverse Reactions (6) and Use in Specific Populations (8.5)].

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.

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.

9.1 Controlled Substance

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) Cmax was 390 (±237) pg/mL, and the mean AUC0-t and AUC0-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 Cmax 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 Cmax 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 Cmax 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)]. 

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.