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Glycopyrronium Cloth

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Glycopyrronium cloth, 2.4% is an anticholinergic drug available as a clear, colorless to pale yellow solution on a single-use pre-moistened cloth (an absorbent polypropylene pad) packaged in a pouch for topical administration. Each pouch contains 105 mg glycopyrronium tosylate, equivalent to 66 mg of glycopyrronium. The inactive ingredients are citric acid, dehydrated alcohol, purified water, and sodium citrate.

Glycopyrronium tosylate is chemically described as pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzensulfonate, hydrate (1:1:1). The structural formula is represented below:

Empirical formula: C26H37NO7S - Molecular weight: 507.6 g/mol

2. INDICATIONS AND USAGE

Glycopyrronium is indicated for topical treatment of primary axillary hyperhidrosis in adult and pediatric patients 9 years of age and older.

3. DOSAGE AND ADMINISTRATION

For topical use only.

Glycopyrronium is for topical use in the underarm area only and not for use in other body areas.

Glycopyrronium is administered by a single-use pre-moistened cloth packaged in individual pouches. Glycopyrronium should be applied to clean dry skin on the underarm areas only. Glycopyrronium should not be used more frequently than once every 24 hours.

Tear open the pouch and pull out the cloth, unfold the cloth, and wipe it across one entire underarm once. Using the same cloth, wipe the other underarm once. A single cloth should be used to apply glycopyrronium to both underarms.

Wash hands immediately with soap and water after applying and discarding the glycopyrronium cloth. Glycopyrronium may cause temporary dilation of the pupils and blurred vision if it comes in contact with the eyes. Avoid transfer of glycopyrronium to the periocular area [see Warnings and Precautions (5.3)].

Do not apply glycopyrronium to broken skin. Avoid using glycopyrronium with occlusive dressings.

4. CONTRAINDICATIONS

Glycopyrronium is contraindicated in patients with medical conditions that can be exacerbated by the anticholinergic effect of glycopyrronium (e.g., glaucoma, paralytic ileus, unstable cardiovascular status in acute hemorrhage, severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, myasthenia gravis, Sjogren’s syndrome).

5. WARNINGS AND PRECAUTIONS

5.1 Worsening of Urinary Retention

Glycopyrronium should be used with caution in patients with a history or presence of documented urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, distended bladder), especially in patients with prostatic hypertrophy or bladder-neck obstruction. Instruct patients to discontinue use immediately and consult a physician should any of these signs or symptoms develop.

Patients with a history of urinary retention were not included in the clinical studies.

5.2 Control of Body Temperature

In the presence of high ambient temperature, heat illness (hyperpyrexia and heat stroke due to decreased sweating) can occur with the use of anticholinergic drugs such as glycopyrronium. Advise patients using glycopyrronium to watch for generalized lack of sweating when in hot or very warm environmental temperatures and to avoid use if not sweating under these conditions.

5.3 Operating Machinery or an Automobile

Transient blurred vision may occur with use of glycopyrronium. If blurred vision occurs, the patient should discontinue use until symptoms resolve. Patients should be warned not to engage in activities that require clear vision such as operating a motor vehicle or other machinery, or performing hazardous work until the symptoms have resolved.

6. ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections

• Worsening of Urinary Retention [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two double-blind, vehicle-controlled clinical trials (Trial 1 [NCT02530281] and Trial 2 [NCT02530294]) of 459 subjects treated with glycopyrronium once daily and 232 treated with vehicle, subjects were 9 to 76 years of age, 47% male, and the percentages of White, Black (including African Americans), and Asian subjects were 82%, 12%, and 1%, respectively.

Table 1 summarizes the most frequent adverse reactions (≥2%) in subjects with primary axillary hyperhidrosis treated with glycopyrronium.

Table 1: Adverse Reactions Occurring in ≥2% of Subjects

Table 2 shows the most frequently reported local skin reactions, which were relatively common in both the glycopyrronium and vehicle groups.

Table 2: Local Skin Reactions

a Patients with a post-baseline local skin reaction assessment

In an open-label safety trial (NCT02553798), 564 subjects were treated for up to an additional 44 weeks after completing Trial 1 or Trial 2. Adverse reactions occurring at a frequency ≥2.0% were: dry mouth (16.9%), vision blurred (6.7%), nasopharyngitis (5.8%), mydriasis (5.3%), urinary hesitation (4.2%), nasal dryness (3.6%), dry eye (2.9%), pharyngitis (2.2%), and application site reactions (pain [6.4%], dermatitis [3.8%], pruritus [3.8%], rash [3.8%], erythema [2.4%]).

7. DRUG INTERACTIONS

7.1 Anticholinergics

Coadministration of glycopyrronium with anticholinergic medications may result in additive interaction leading to an increase in anticholinergic adverse effects [see Warnings and Precautions (5) and Adverse Reactions (6)]. Avoid coadministration of glycopyrronium with other anticholinergic-containing drugs.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on glycopyrronium use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. In pregnant rats, daily oral administration of glycopyrrolate (glycopyrronium bromide) during organogenesis did not result in an increased incidence of gross external or visceral defects [see Data]. When glycopyrrolate was administered intravenously to pregnant rabbits during organogenesis, no adverse effects on embryo-fetal development were seen. The available data do not support relevant comparisons of systemic glycopyrronium exposures achieved in the animal studies to exposures observed in humans after topical use of glycopyrronium.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Glycopyrrolate was orally administered to pregnant rats at dosages of 50, 200, and 400 mg/kg/day during the period of organogenesis. Glycopyrrolate had no effect on maternal survival, but significantly reduced mean maternal body weight gain over the period of dosing at all dosages evaluated. Mean fetal weight was significantly reduced in the 200 and 400 mg/kg/day dose groups. There were two litters with all resorbed fetuses in the 400 mg/kg/day dose group. There were no effects of treatment on the incidence of gross external or visceral defects. Minor treatment-related skeletal effects included reduced ossification of various bones in the 200 and 400 mg/kg/day dose groups; these skeletal effects were likely secondary to maternal toxicity.

Glycopyrrolate was intravenously administered to pregnant rabbits at dosages of 0.1, 0.5, and 1.0 mg/kg/day during the period of organogenesis. Glycopyrrolate did not affect maternal survival under the conditions of this study. Mean maternal body weight gain and mean food consumption over the period of dosing were lower than the corresponding control value in the 0.5 and 1.0 mg/kg/day treatment groups. There were no effects of treatment on fetal parameters, including fetal survival, mean fetal weight, and the incidence of external, visceral, or skeletal defects.

Female rats that were pregnant or nursing were orally dosed with glycopyrrolate daily at dosages of 0, 50, 200, or 400 mg/kg/day, beginning on day 7 of gestation, and continuing until day 20 of lactation. Mean body weight of pups in all treatment groups was reduced compared to the control group during the period of nursing, but eventually recovered to be comparable to the control group, post-weaning. No other notable delivery or litter parameters were affected by treatment in any group, including no effects on mean duration of gestation or mean numbers of live pups per litter. No treatment-related effects on survival or adverse clinical signs were observed in pups. There were no effects of maternal treatment on behavior, learning, memory, or reproductive function of pups.

8.2 Lactation

Risk Summary

There are no data on the presence of glycopyrrolate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for glycopyrronium and any potential adverse effects on the breastfed infant from glycopyrronium or from the underlying maternal condition.

8.4 Pediatric Use

The safety, effectiveness and pharmacokinetics of glycopyrronium have been established in pediatric patients age 9 years and older for topical treatment of primary axillary hyperhidrosis [see Clinical Pharmacology]. Use of glycopyrronium in this age group is supported by evidence from two multicenter, randomized, double-blind, parallel-group, vehicle-controlled 4-week trials which included 34 pediatric subjects 9 years and older [see Adverse Reactions (6.1) and Clinical Studies]. The safety and effectiveness of glycopyrronium have not been established in pediatric patients under 9 years of age.

8.5 Geriatric Use

Clinical trials of glycopyrronium did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects.

8.6 Renal Impairment

The elimination of glycopyrronium is severely impaired in patients with renal failure [see Clinical Pharmacology].

9. OVERDOSAGE

Because glycopyrronium is a quaternary amine which does not easily cross the blood-brain barrier, symptoms of glycopyrronium overdosage are generally more peripheral in nature rather than central compared to other anticholinergic agents. Associated signs and symptoms related to excessive anticholinergic activity may include flushing, hyperthermia, tachycardia, ileus, urinary retention, loss of ocular accommodation and light sensitivity due to mydriasis.

In the case of overdose when symptoms are severe or life threatening, therapy may include:

• Managing per standard of care any acute conditions such as hyperthermia, coma, and/or seizures, as applicable, and managing any myoclonic or choreoathetoid movements which may lead to rhabdomyolysis in some cases of anticholinergic overdosage

• Managing severe urinary retention with catheterization if not spontaneously reversed within several hours

• Providing cardiovascular support and/or controlling arrhythmias

• Maintaining an open airway, providing ventilation as necessary

• Administering a quaternary ammonium anticholinesterase such as neostigmine to help alleviate severe and/or life threatening peripheral anticholinergic effects.

Topical overdosing of glycopyrronium could result in an increased incidence or severity of local skin reactions. Administration of glycopyrronium under occlusive conditions may result in an increase in anticholinergic effects, including dry mouth and urinary hesitation.

10. MECHANISM OF ACTION

Glycopyrronium is a competitive inhibitor of acetylcholine receptors that are located on certain peripheral tissues, including sweat glands. In hyperhidrosis, glycopyrronium inhibits the action of acetylcholine on sweat glands, reducing sweating.

11. PHARMACODYNAMICS

The pharmacodynamics of glycopyrronium are not known.

12. PHARMACOKINETICS

Absorption

The pharmacokinetics of glycopyrronium were evaluated in adult and pediatric patients with primary axillary hyperhidrosis following Qbrexza once daily applied to the axillae for 5 days. The mean ± SD exposures of glycopyrronium are presented in Tables 3 and 4. There was no evidence of accumulation.

Table 3: Mean ± SD Plasma Exposures of Glycopyrronium in Adults Following Qbrexza Once Daily for 5 days

Abbreviations: Maximum concentration (Cmax), Area under the time concentration curve (AUC) between 0 and 6 hours following administration of Qbrexza (AUC0-6h), AUC between 0 and 24 hours following administration of Qbrexza (AUC0-24h)

Distribution

After IV administration, glycopyrronium has a mean volume of distribution in children aged 1 to 14 years of approximately 1.3 to 1.8 L/kg, with a range from 0.7 to 3.9 L/kg. In adults aged 60-75 years, the volume of distribution was lower (0.42 L/kg ± 0.22).

Elimination

Metabolism

A small proportion of glycopyrronium is metabolized following IV administration. The metabolic pathway for glycopyrronium is not characterized.

Excretion

Following administration of a single radiolabeled IV glycopyrronium dose to adult subjects who underwent surgery for cholelithiasis, approximately 85% of total radioactivity was excreted in urine and < 5% was present in bile drainage. Greater than 80% of the radioactivity in both urine and bile was unchanged drug.

Specific Populations

The pharmacokinetics of glycopyrronium were not evaluated in pregnant women or patients with hepatic impairment.

Pediatric Subjects

The mean ± SD exposures of glycopyrronium in pediatric subjects following Qbrexza once daily for 5 days are presented in Table 4. There was no evidence of accumulation.

Table 4: Mean ± SD Plasma Exposures of Glycopyrronium in Pediatric Subjects Aged 10 to 17 years Following Qbrexza Once Daily for 5 days

Patients with Renal Impairment

Following a 4 mcg/kg IV dose of a glycopyrronium formulation for IV use, mean glycopyrronium AUC (10.6 mcg·h/L), CL (0.43 L/h/kg) and 3-hour urinary excretion (0.7%) were significantly different in uremic subjects undergoing renal transplantation surgery than those of healthy subjects (3.73 mcg·h/L, 1.14 L/h/kg, and 50%, respectively).

Pharmacokinetics of Qbrexza in subjects with renal impairment has not been studied.

In Vitro Studies

In vitro studies indicated that under the conditions of clinical use, Qbrexza is not expected to induce cytochrome P450 (CYP) enzymes 1A2, 2B6 and 3A4; or inhibit 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

Qbrexza (glycopyrronium) cloth is supplied as:

A single-use cloth pre-moistened with a 2.4% glycopyrronium solution in a pouch

Carton of 30 pouches NDC 70428-011-12

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Qbrexza is flammable; keep away from heat or flame.

Rx only

Rev 06/18