CUVPOSA- glycopyrrolate liquid
Merz Pharmaceuticals, LLC
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use CUVPOSA ® safely and effectively. See full prescribing information for CUVPOSA.
CUVPOSA (glycopyrrolate) oral solution
Initial U.S. Approval: 1961
INDICATIONS AND USAGE
CUVPOSA is an anticholinergic indicated to reduce chronic severe drooling in patients aged 3-16 years with neurologic conditions associated with problem drooling (e.g., cerebral palsy). (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
1 mg/5 mL, oral solution in 16 ounce bottles. (3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions (incidence ≥30%) are dry mouth, vomiting, constipation, flushing, and nasal congestion. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 866-862-1211 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
CUVPOSA is indicated to reduce chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling (e.g., cerebral palsy).
CUVPOSA must be measured and administered with an accurate measuring device [see Patient Counseling Information (17)].
Initiate dosing at 0.02 mg/kg orally three times daily and titrate in increments of 0.02 mg/kg every 5-7 days based on therapeutic response and adverse reactions. The maximum recommended dosage is 0.1 mg/kg three times daily not to exceed 1.5-3 mg per dose based upon weight. For greater detail, see Table 1.
During the four-week titration period, dosing can be increased with the recommended dose titration schedule while ensuring that the anticholinergic adverse events are tolerable. Prior to each increase in dose, review the tolerability of the current dose level with the patient's caregiver.
CUVPOSA should be dosed at least one hour before or two hours after meals.
The presence of high fat food reduces the oral bioavailability of CUVPOSA if taken shortly after a meal [see Clinical Pharmacology (12.3)].
|Weight||Dose Level 1||Dose Level 2||Dose Level 3||Dose Level 4||Dose Level 5|
|kg||lbs||(~0.02 mg/kg)||(~0.04 mg/kg)||(~0.06 mg/kg)||(~0.08 mg/kg)||(~0.1 mg/kg)|
|13-17||27-38||0.3 mg||1.5 mL||0.6 mg||3 mL||0.9 mg||4.5 mL||1.2 mg||6 mL||1.5 mg||7.5 mL|
|18-22||39-49||0.4 mg||2 mL||0.8 mL||4 mL||1.2 mg||6 mL||1.6 mg||8 mL||2.0 mg||10 mL|
|23-27||50-60||0.5 mg||2.5 mL||1.0 mg||5 mL||1.5 mg||7.5 mL||2.0 mg||10 mL||2.5 mg||12.5 mL|
|28-32||61-71||0.6 mg||3 mL||1.2 mg||6 mL||1.8 mg||9 mL||2.4 mg||12 mL||3.0 mg||15 mL|
|33-37||72-82||0.7 mg||3.5 mL||1.4 mg||7 mL||2.1 mg||10.5 mL||2.8 mg||14 mL||3.0 mg||15 mL|
|38-42||83-93||0.8 mg||4 mL||1.6 mg||8 mL||2.4 mg||12 mL||3.0 mg||15 mL||3.0 mg||15 mL|
|43-47||94-104||0.9 mg||4.5 mL||1.8 mg||9 mL||2.7 mg||13.5 mL||3.0 mg||15 mL||3.0 mg||15 mL|
|≥48||≥105||1.0 mg||5 mL||2.0 mg||10 mL||3.0 mg||15 mL||3.0 mg||15 mL||3.0 mg||15 mL|
CUVPOSA is available as a 1mg/5 mL clear, cherry-flavored solution for oral administration in 16 ounce bottles.
CUVPOSA is contraindicated in:
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.
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.
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.
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.
Use CUVPOSA with caution in patients with conditions that are exacerbated by anticholinergic drug effects including:
The following serious adverse reactions are described elsewhere in the labeling:
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.
|Dry Mouth||8 (40%)||2 (11%)|
|Vomiting||8 (40%)||2 (11%)|
|Constipation||7 (35%)||4 (22%)|
|Flushing||6 (30%)||3 (17%)|
|Nasal Congestion||6 (30%)||2 (11%)|
|Headache||3 (15%)||1 (6%)|
|Sinusitis||3 (15%)||1 (6%)|
|Upper Respiratory Tract Infection||3 (15%)||0|
|Urinary Retention||3 (15%)||0|
The following adverse reactions occurred at a rate of <2% of patients receiving CUVPOSA in the open-label study.
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 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.
Drugs Whose Plasma Levels May be Decreased by Glycopyrrolate
Coadministration of glycopyrrolate may result in decreased levels of certain drugs.
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.
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 AUC0-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 AUC0-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 AUC0-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.
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.
Because glycopyrrolate is largely renally eliminated, CUVPOSA should be used with caution in patients with renal impairment [see Clinical Pharmacology (12.3)].
Because glycopyrrolate is a quaternary amine which does not easily cross the blood-brain barrier, symptoms of glycopyrrolate overdosage are generally more peripheral in nature rather than central compared to other anticholinergic agents. In case of accidental overdose, therapy may include:
CUVPOSA is an anticholinergic drug available as an oral solution containing 1 mg glycopyrrolate per 5 mL. The chemical name for glycopyrrolate is pyrrolidinium, 3-[(cyclopentylhydroxyphenylacetyl) oxy]-1,1-dimethyl-,bromide. The chemical structure is:
The empirical formula for CUVPOSA is C19H28BrNO3 and the molecular weight is 398.33. The inactive ingredients in CUVPOSA are: citric acid, glycerin, natural and artificial cherry flavor, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate, sorbitol solution, and purified water.
Glycopyrrolate is a competitive inhibitor of acetylcholine receptors that are located on certain peripheral tissues, including salivary glands. Glycopyrrolate indirectly reduces the rate of salivation by preventing the stimulation of these receptors.
Glycopyrrolate inhibits the action of acetylcholine on salivary glands thereby reducing the extent of salivation.
In a parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery, subjects received either intravenous (IV) or oral glycopyrrolate as a premedication. The mean absolute bioavailability of oral glycopyrrolate tablets was low (approximately 3%) and highly variable among subjects (range 1.3 to 13.3%). A similar pattern of low and variable relative bioavailability is seen in adults.
Analysis of population pharmacokinetic data from normal adults and children with cerebral palsy associated chronic moderate to severe drooling failed to demonstrate linear pharmacokinetics across the dose range. In the same analysis, population estimates of the apparent oral clearance (scaled by weight in children and adults) ranged from 5.28 - 38.95 L/hr/kg for healthy adults and 8.07 - 25.65 L/hr/kg for patients with cerebral palsy, a reflection of the low and highly variable oral bioavailability of glycopyrrolate.
Absorption of CUVPOSA (fasting) was compared to that of a marketed glycopyrrolate oral tablet. The Cmax after oral solution administration was 23% lower compared to tablet administration and AUC0-inf was 28% lower after oral solution administration. Mean Cmax after oral solution administration in the fasting state was 0.318 ng/mL, and mean AUC0-24 was 1.74 ng∙hr/mL. Mean time to maximum plasma concentration for CUVPOSA was 3.1 hours, and mean plasma half-life was 3.0 hours.
In healthy adults, a high fat meal was shown to significantly affect the absorption of glycopyrrolate oral solution (10 mL, 1 mg/5 mL). The mean Cmax under fed high fat meal conditions was approximately 74% lower than the Cmax observed under fasting conditions. Similarly, mean AUC0-T was reduced by about 78% by the high fat meal compared with the fasting AUC0-T. A high fat meal markedly reduces the oral bioavailability of CUVPOSA. Therefore, CUVPOSA should be dosed at least one hour before or two hours after meals. Pharmacokinetic results (mean ± SD) are described in Table 3.
|0.318 ± 0.190||3.10 ± 1.08||1.74 ± 1.07||1.81 ± 1.09||3.0 ± 1.2|
|0.084 ± 0.081||2.60 ± 1.12||0.38 ± 0.14||0.46 ± 0.13*||3.2 ± 1.1*|
After IV administration, glycopyrrolate 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).
In adult patients who underwent surgery for cholelithiasis and were given a single IV dose of tritiated glycopyrrolate, approximately 85% of total radioactivity was excreted in urine and <5% was present in T-tube drainage of bile. In both urine and bile, >80% of the radioactivity corresponded to unchanged drug. These data suggest a small proportion of IV glycopyrrolate is excreted as one or more metabolites.
Approximately 65-80% of an IV glycopyrrolate dose was eliminated unchanged in urine in adults. In two studies, after IV administration to pediatric patients ages 1-14 years, mean clearance values ranged from 1.01- 1.41 L/kg/hr (range 0.32 -2.22 L/kg/hr). In adults, IV clearance values were 0.54 ± 0.14 L/kg/hr.
The estimated apparent clearance of glycopyrrolate from a population pharmacokinetic analysis (scaled by weight in children and adults) of oral and IV data was found to be 13.2 L/hr/kg or 92.7 L/hr for a typical 70 kg subject. In the same population based analysis, gender was not identified as having an effect on either glycopyrrolate clearance or systemic exposure.
Population pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or systemic exposure.
In one study, glycopyrrolate 4 mcg/kg was administered intravenously in uremic patients undergoing renal transplantation surgery. Mean AUC (10.6 mcg∙h/L), mean plasma clearance (0.43 L/hr/kg) and mean 3-hour urinary excretion (0.7%) for glycopyrrolate were significantly different than those of control patients (3.73 µg∙h/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that elimination of glycopyrrolate is severely impaired in patients with renal failure.
When glycopyrrolate was administered via oral gavage to mice for up to 24 months at dosages of 2.5, 7, and 20 mg/kg/day in both genders, resulting in systemic exposures (estimated AUC0-inf values) approximately 0.1, 0.3, and 0.8 times, respectively, the estimated systemic exposure in humans at the MRHD (9 mg per day, administered in three divided doses), no significant changes in tumor incidence were observed when compared to control.
When glycopyrrolate was administered via oral gavage to rats for up to 24 months at dosages of 5, 15, and 40 mg/kg/day in both genders, resulting in systemic exposures approximately 0.2, 0.8, and 2 times, respectively, the estimated systemic exposure in humans at the MRHD, no significant changes in tumor incidence were observed when compared to control.
Glycopyrrolate did not elicit any genotoxic effects in the Ames mutagenicity assay, the human lymphocyte chromosome aberration assay, or the micronucleus assay.
Glycopyrrolate was assessed for effects on fertility or general reproductive function in rats. Rats of both genders received glycopyrrolate at dosages up to 100 mg/kg/day via oral gavage, resulting in systemic exposures (estimated AUC0-inf values) in males and females up to approximately 11 and 15 times, respectively, the estimated systemic exposure in humans at the MRHD. No treatment-related effects on fertility or reproductive parameters were observed in either gender in this study.
CUVPOSA was evaluated in a multi-center, randomized, double-blind, placebo-controlled, parallel, eight-week study for the control of pathologic drooling in children (Study 1). The study enrolled 38 subjects aged 3-23 years; thirty-six subjects were aged 3-16 years and two patients were greater than 16 years. The subjects were male or female, weighed at least 13 kg (27 lbs), and had cerebral palsy, mental retardation, or another neurologic condition associated with problem drooling defined as drooling in the absence of treatment so that clothing became damp on most days (approximately five to seven days per week). Subjects were randomized in a 1:1 fashion to receive CUVPOSA or placebo. Doses of study medication were titrated over a 4-week period to optimal response beginning at 0.02 mg/kg three times a day increasing doses in increments of approximately 0.02 mg/kg three times per day every 5-7 days, not to exceed the lesser of approximately 0.1 mg/kg three times per day or 3 mg three times per day.
Subjects were evaluated on the 9-point modified Teacher's Drooling Scale (mTDS), which is presented below. The mTDS evaluations were recorded by parents/caregivers 3 times daily approximately two hours post-dose on evaluation days during pre-treatment baseline and at Weeks 2, 4, 6 and 8 of therapy.
Modified Teacher's Drooling Scale
1= Dry: never drools
2= Mild: only the lips are wet; occasionally
3= Mild: only the lips are wet; frequently
4= Moderate: wet on the lips and chin; occasionally
5= Moderate: wet on the lips and chin; frequently
6= Severe: drools to the extent that clothing becomes damp; occasionally
7= Severe: drools to the extent that clothing becomes damp; frequently
8= Profuse: clothing, hands, tray, and objects become wet; occasionally
9= Profuse: clothing, hands, tray, and objects become wet; frequently
Responders were defined as subjects with at least a 3-point reduction in mean daily mTDS scores from baseline to Week 8. Table 4 presents the proportion of responders at Week 8 and Figure 1 presents the mean mTDS values from baseline through Week 8.
|15/20 (75%)||2/18 (11%)|
NDC 0259-0501-16; 1 mg/5mL clear, cherry-flavored solution; 16 oz. bottle.
Atlanta, GA 30318
Merz North America, Inc.
Raleigh, NC 27615
© 2017 Merz Pharmaceuticals, LLC
CUVPOSA® is a registered trademark of Merz Pharmaceuticals, LLC
PATIENT and CAREGIVER INFORMATION
CUVPOSA (glycopyrrolate) Oral Solution
Please read the Patient and Caregiver Information that comes with CUVPOSA before you start giving it to your child, and each time you get a refill. This leaflet does not take the place of talking with your doctor about your child's medical condition or treatment.
What is CUVPOSA?
CUVPOSA is a prescription medicine used in children with medical conditions that cause too much (abnormal) drooling.
Who should not take CUVPOSA?
Do not give CUVPOSA to anyone who:
What should I tell my doctor before giving CUVPOSA to my child?
Tell your doctor if your child:
Tell your doctor about all of the medicines that your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicine may affect the way CUVPOSA works, and CUVPOSA may affect how some other medicines work.
How should I give CUVPOSA?
What should I avoid while taking CUVPOSA?
CUVPOSA can cause serious side effects including:
The most common side effects of CUVPOSA include:
Tell your doctor if your child has any side effect that concerns you or that does not go away. These are not all the possible side effects of CUVPOSA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store CUVPOSA?
Store CUVPOSA between 68°F to 77°F (20°C to 25°C).
Keep CUVPOSA out of the reach of children.
General information about CUVPOSA:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CUVPOSA for a condition for which it was not prescribed. Do not give CUVPOSA to other people even if they have the same condition. It may harm them.
This leaflet summarizes the most important information about CUVPOSA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CUVPOSA that is written for health professionals.
For more information, go to: www.cuvposa.com or call 866-862-1211.
What are the ingredients in CUVPOSA?
Active Ingredient: glycopyrrolate
Inactive Ingredients: citric acid, glycerin, natural and artificial cherry flavor, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate, sorbitol solution, and purified water
Issued May 2011
Atlanta, GA 30318
Merz North America, Inc.
Raleigh, NC 27615
© 2017 Merz Pharmaceuticals, LLC
CUVPOSA® is a registered trademark of Merz Pharmaceuticals, LLC
|Labeler - Merz Pharmaceuticals, LLC (126209282)|