CUVPOSA Oral solution Ref.[10794] Active ingredients: Glycopyrronium

5.1 Constipation or Intestinal Pseudo-obstruction

Constipation is a common dose-limiting adverse reaction which sometimes leads to glycopyrrolate discontinuation [see Adverse Reactions (6.1)]. Assess patients for constipation, particularly within 4-5 days of initial dosing or after a dose increase. Intestinal pseudo-obstruction has been reported and may present as abdominal distention, pain, nausea or vomiting.

5.2 Incomplete Mechanical Intestinal Obstruction

Diarrhea may be an early symptom of incomplete mechanical intestinal obstruction, especially in patients with ileostomy or colostomy. If incomplete mechanical intestinal obstruction is suspected, discontinue treatment with CUVPOSA and evaluate for intestinal obstruction.

5.3 High Ambient Temperatures

In the presence of high ambient temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with the use of anticholinergic drugs such as CUVPOSA. Advise patients/caregivers to avoid exposure of the patient to hot or very warm environmental temperatures.

5.4 Operating Machinery or an Automobile

CUVPOSA may produce drowsiness or blurred vision. As appropriate for a given age, warn the patient not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or performing hazardous work while taking CUVPOSA.

5.5 Anticholinergic Drug Effects

Use CUVPOSA with caution in patients with conditions that are exacerbated by anticholinergic drug effects including:

• Autonomic neuropathy
• Renal disease
• Ulcerative colitis – Large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason may precipitate or aggravate “toxic megacolon”, a serious complication of the disease
• Hyperthyroidism
• Coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, and hypertension
• Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition

The following serious adverse reactions are described elsewhere in the labeling:

• Constipation or intestinal pseudo-obstruction [see Warnings and Precautions (5.1)]
• Incomplete mechanical intestinal obstruction [see Warnings and Precautions (5.2)]

The most common adverse reactions reported with CUVPOSA are dry mouth, vomiting, constipation, flushing, and nasal congestion.

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.

The data described below reflect exposure to CUVPOSA in 151 subjects, including 20 subjects who participated in an 8-week placebo-controlled study (Study 1) and 137 subjects who participated in a 24-week open-label study (six subjects who received CUVPOSA in the placebo-controlled study and 131 new subjects).

Table 2 presents adverse reactions reported by ≥15% of CUVPOSA-treated subjects from the placebo-controlled clinical trial.

Table 2. Adverse Reactions Occurring in ≥15% of CUVPOSA-Treated Subjects and at a Greater Frequency than Placebo in Study 1:

The following adverse reactions occurred at a rate of <2% of patients receiving CUVPOSA in the open-label study.

• Gastrointestinal: Abdominal distention, abdominal pain, stomach discomfort, chapped lips, flatulence, retching, dry tongue
• General Disorders: Irritability, pain
• Infections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract infection
• Investigations: Heart rate increase
• Metabolism and Nutrition: Dehydration
• Nervous System: Headache, convulsion, dysgeusia, nystagmus
• Psychiatric: Agitation, restlessness, abnormal behavior, aggression, crying, impulse control disorder, moaning, mood altered
• Respiratory: Increased viscosity of bronchial secretion, nasal congestion, nasal dryness
• Skin: Dry skin, pruritus, rash
• Vascular: Pallor

The following adverse reactions have been identified during postapproval use of other formulations of glycopyrrolate for other indications. Because 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.

Additional adverse reactions identified during postapproval use of glycopyrrolate tablets include: loss of taste and suppression of lactation.

Drugs Affected by Reduced GI Transit Time

Glycopyrrolate reduces GI transit time, which may result in altered release of certain drugs when formulated in delayed- or controlled-release dosage forms.

• The passage of potassium chloride tablets through the GI tract may be arrested or delayed with coadministration of glycopyrrolate. Solid dosage forms of potassium chloride are contraindicated [see Contraindications (4)].
• Digoxin administered as slow dissolution oral tablets may have increased serum levels and enhanced action when administered with glycopyrrolate. Monitor patients receiving slow dissolution digoxin for increased action if glycopyrrolate is coadministered regularly. Consider the use of other oral dosage forms of digoxin (e.g., elixir or capsules).

Amantadine

The anticholinergic effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the dose of glycopyrrolate during coadministration of amantadine.

Drugs Whose Plasma Levels May be Increased by Glycopyrrolate

Coadministration of glycopyrrolate may result in increased levels of certain drugs.

• Atenolol’s bioavailability may be increased with coadministration of glycopyrrolate. A reduction in the atenolol dose may be needed.
• Metformin plasma levels may be elevated with coadministration of glycopyrrolate, increasing metformin’s pharmacologic and toxic effects. Monitor clinical response to metformin with concomitant glycopyrrolate administration; consider a dose reduction of metformin if warranted.

Drugs Whose Plasma Levels May be Decreased by Glycopyrrolate

Coadministration of glycopyrrolate may result in decreased levels of certain drugs.

• Haloperidol’s serum level may be decreased when coadministered with glycopyrrolate, resulting in worsening of schizophrenic symptoms, and development of tardive dyskinesia. Closely monitor patients if coadministration cannot be avoided.
• Levodopa’s therapeutic effect may be reduced with glycopyrrolate administration. Consider increasing the dose of levodopa.

Risk Summary

There are no available data in pregnant women for Cuvposa to inform decisions concerning any drug-associated risks. In pregnant rats, daily oral administration of glycopyrrolate during organogenesis at dose exposures 2.5 to 113 times the exposure at the maximum recommended human dose (MRHD) 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 at dose exposures equivalent to up to approximately 7.8 times the exposure at the MRHD, no adverse effects on embryo-fetal development were seen. The estimated background risk of major birth defects and miscarriage for the indicated population is 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.

Animal Data

Glycopyrrolate was orally administered to pregnant rats at dosages of 50, 200, and 400 mg/kg/day during the period of organogenesis. These dosages resulted in systemic exposures (estimated AUC_0-inf values) approximately 2.5, 23, and 113 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses). 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. These dosages resulted in systemic exposures (estimated AUC_0-inf values) approximately 0.8, 4.6, and 7.8 times, respectively, the estimated systemic exposure in humans at the MRHD. 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. These dosages resulted in systemic exposures (estimated AUC_0-inf values) approximately 2.5, 23, and 113 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses). 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.

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 CUVPOSA and any potential adverse effects on the breastfed infant from CUVPOSA or from the underlying maternal condition.

CUVPOSA was evaluated for chronic severe drooling in patients aged 3-16 years with neurologic conditions associated with problem drooling. CUVPOSA has not been studied in subjects under the age of 3 years.

Clinical studies of CUVPOSA did not include subjects aged 65 and over.

Because glycopyrrolate is largely renally eliminated, CUVPOSA should be used with caution in patients with renal impairment [see Clinical Pharmacology (12.3)].