Dartisla ODT

DARTISLA ODT
(glycopyrrolate) orally disintegrating tablets

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 C₁₉H₂₈BrNO₃, the molecular weight is 398.3 g/mol, and the structural formula is:

Each DARTISLA ODT contains: glycopyrrolate, USP 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.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

Important Dosing Information

• 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 [seeDosage Forms And Strengths一个dCLINICAL PHARMACOLOGY].
• DARTISLA ODT is not recommended for patients in whom a lower dosage strength of another oral glycopyrrolate product (e.g., tablet strength of 1 mg) is appropriate for initial or maintenance treatment because the dosage strength of DARTISLA ODT may exceed the recommended initial and maintenance dosage of other oral glycopyrrolate products.

Recommended Dosage

• The recommended dosage of DARTISLA ODT is 1.7 mg given two or three times daily administered on top of the tongue. Allow the tablet to disintegrate and swallow without water [seeCLINICAL PHARMACOLOGY].
• The maximum recommended daily dosage of DARTISLA ODT is 6.8 mg.
• Administer DARTISLA ODT at least one hour before or two hours after food [seeCLINICAL PHARMACOLOGY].
• Use the lowest effective dosage of glycopyrrolate to control symptoms. Switch patients who can be titrated to a lower dose of oral glycopyrrolate to another oral tablet dosage form of glycopyrrolate.

Administration Instructions

• 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.

HOW SUPPLIED

Dosage Forms And Strengths

Orally Disintegrating Tablets: 1.7 mg of glycopyrrolate, white to off-white, round, and debossed with the symbol.

Storage And Handling

DARTISLA ODTis supplied as 1.7 mg glycopyrrolate as a white to off-white, round orally disintegrating tablets debossed with the symbol Available as:

NDC82111-518-01: 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].

Manufactured by: Catalent Pharma Solutions Limited Frankland Road Blagrove, Swindon Wiltshire SN5 8RU, United Kingdom (GBR). Manufactured for: Edenbridge Pharmaceuticals, LLC Parsippany, NJ 07054. Revised: Dec 2021.

SIDE EFFECTS

The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:

• Precipitation of AcuteGlaucoma[seeWARNINGS AND PRECAUTIONS]
• Partial or Complete MechanicalIntestinal Obstruction[seeWARNINGS AND PRECAUTIONS]
• GastrointestinalAdverse Reactions due to Decreased Gastrointestinal Motility [seeWARNINGS AND PRECAUTIONS]
• Cognitive一个d Visual Adverse Reactions [seeWARNINGS AND PRECAUTIONS]
• Heat Prostrationat High Environmental Temperatures [seeWARNINGS AND PRECAUTIONS]
• Other Conditions Exacerbated byAnticholinergicAdverse Reactions [seeWARNINGS AND PRECAUTIONS]
• Increased Risk of Anticholinergic Adverse Reactions in Geriatric Patients [seeWARNINGS AND PRECAUTIONS]

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,dilatationof thepupil, increasedoculartension

Gastrointestinal Disorders:bloated feeling, constipation,dry mouth,dysgeusia, nausea, vomiting

免疫系统疾病:一个aphylaxis[seeCONTRAINDICATIONS]

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

DRUG INTERACTIONS

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, antispasmodics, amantadine) resulting in increased anticholinergic adverse reactions. Coadministration of antipsychotics with glycopyrrolate may lead to worsening oftardive dyskinesia．DARTISLA ODT is not recommended in patients taking other anticholinergic drugs [seeWARNINGS AND PRECAUTIONS].

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 [seeWARNINGS AND PRECAUTIONS].

Gastrointestinal Toxicity With Solid Oral Dosage Forms Of Potassium Chloride

Oral glycopyrrolate may worsen gastrointestinal mucosal injury reported with solid oral dosage forms ofpotassiumchloride due to decreasedgastricmotility and increased transit time leading to prolonged contact with the gastrointestinalmucosa．DARTISLA ODT is not recommended in patients taking solid oral dosage forms of potassium chloride.

WARNINGS

Included as part of thePRECAUTIONSsection.

PRECAUTIONS

Precipitation Of Acute Glaucoma

Glycopyrrolate may cause increasedintraocular pressurein 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) [seeCONTRAINDICATIONS].

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 withileostomyorcolostomy．If partial or complete intestinal obstruction is suspected, discontinue use of DARTISLA ODT and evaluate for potential intestinal obstruction [seeCONTRAINDICATIONS].

Gastrointestinal Adverse Reactions Due To Decreased Gastrointestinal Motility

Glycopyrrolate reduces gastrointestinal motility and may result in delayed gastric emptying, constipation, andintestinal pseudo-obstruction一个d may precipitate or aggravateparalytic ileus一个dtoxic megacolon[seeCONTRAINDICATIONS]. The risk of gastrointestinal adverse reactions is further increased with use of other anticholinergics and other medications that decrease gastrointestinalperistalsis．Monitor patients for symptoms of decreased gastrointestinal motility. Concomitant use of DARTISLA ODT and other anticholinergics or other medications that decreaseGIperistalsis is not recommended [seeDRUG INTERACTIONS].

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 [seeADVERSE REACTIONS]. Concomitant use of other drugs that have anticholinergic properties may increase these effects [seeDRUG INTERACTIONS]. 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.

Heat Prostration At High Environmental Temperatures

In the presence of a high environmental temperature, heat prostration resulting in fever andheat strokecan occur with use of DARTISLA ODT due to decreased sweating, particularly in geriatric patients [seeADVERSE REACTIONS]. Advise patients to avoid exposure to hot or very warm environmental temperatures when taking DARTISLA ODT. DARTISLA ODT is not recommended in geriatric patients [seeWARNINGS AND PRECAUTIONS].

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, andhiatal herniaassociated withrefluxesophagitis) and in patients taking other anticholinergic medications [seeDRUG INTERACTIONS].

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 [seeCONTRAINDICATIONS,WARNINGS AND PRECAUTIONS,ADVERSE REACTIONS一个dUse In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Reproduction studies in rats resulted in diminished rates ofconception, 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.

Use In Specific Populations

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 (seeData).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk ofbirth 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 [seeNonclinical Toxicology].

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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 [seeCONTRAINDICATIONS一个dWARNINGS AND PRECAUTIONS].

Renal Impairment

Glycopyrrolate is substantially excreted by the kidney [seeCLINICAL PHARMACOLOGY]. Monitor patients with renal impairment for anticholinergic adverse reactions [seeADVERSE REACTIONS]. If anticholinergic adverse reactions occur, discontinue DARTISLA ODT.

OVERDOSE

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 ocularaccommodation一个d light sensitivity due tomydriasis), butcentral nervous systemtoxicity (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 andcardiovascularmonitoring and support. Consider administration ofactivated charcoal一个d/or use of a reversible anticholinesterase as appropriate or recommended by Poison Control.

CONTRAINDICATIONS

DARTISLA ODT is contraindicated in:

• Patients at risk for anticholinergic toxicity due to an underlying medical condition, including:
  • Glaucoma [seeWARNINGS AND PRECAUTIONS]
  • Obstructive uropathies including prostatichypertrophy
  • Mechanical obstructive diseases ofgastrointestinal tract(e.g., pyloroduodenalstenosis, strictures) [seeWARNINGS AND PRECAUTIONS]
  • Gastrointestinal motility disorders (e.g.,achalasia, paralytic ileus, intestinal atony) [seeWARNINGS AND PRECAUTIONS]
  • Bleeding gastrointestinal ulcer
  • Active inflammatory or infectiouscolitiswhich can lead to toxicmegacolon
  • History of or current toxic megacolon
  • Myasthenia gravis
• Patients with a hypersensitivity to glycopyrrolate or any of the inactive ingredients in DARTISLA ODT [seeADVERSE REACTIONS一个dDESCRIPTION].

CLINICAL PHARMACOLOGY

Mechanism Of Action

Glycopyrrolate, an anticholinergic (antimuscarinic) agent, inhibits the action ofacetylcholineonparietalcells in the stomach and decreases the volume and acidity of gastric secretions.

Pharmacodynamics

没有正式conduc药效学研究ted with DARTISLA ODT.

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•h/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 [seeDOSAGE AND ADMINISTRATION].

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 [seeDOSAGE AND ADMINISTRATION].

Effect Of Food

In healthy adults, a high-fat, high-caloriemeal (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 [seeDOSAGE AND ADMINISTRATION].

Elimination

After DARTISLA ODT 1.7 mg administration, the mean plasma half-life was 2.8 hours.

Specific Populations

Patients With Renal Impairment

发表的文献中,胃长宁4微克/公斤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) [seeUse In Specific Populations].

PATIENT 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) [seeWARNINGS AND PRECAUTIONS].

Partial Or Complete Mechanical Intestinal Obstruction

Advise patients to contact their healthcare provider if diarrhea occurs, especially in patients with ileostomy or colostomy [seeWARNINGS AND PRECAUTIONS].

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, abdominaldistention, and constipation [seeWARNINGS AND PRECAUTIONS].

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) [seeWARNINGS AND PRECAUTIONS].

Heat Prostration At High Environmental Temperatures

Inform patients that DARTISLA ODT can reduce sweating, leading to the possibility ofheat exhaustionor heatstroke．建议患者不要接触热或非常warm environmental temperatures [seeWARNINGS AND PRECAUTIONS].

Dosage And Administration Instructions

• Administer DARTISLA ODT at least one hour before or two hours after food [seeDOSAGE AND ADMINISTRATION].
• 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 [seeDOSAGE AND ADMINISTRATION].