Cuvposa
(Glycopyrrolate)Dosage & Administration
CUVPOSA must be measured and administered with an accurate measuring device [see
See FDA-approved patient labeling (Patient Information)
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
| 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 |
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
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 Cmaxafter oral solution administration was 23% lower compared to tablet administration and AUC0-infwas 28% lower after oral solution administration. Mean Cmaxafter oral solution administration in the fasting state was 0.318 ng/mL, and mean AUC0-24was 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 Cmaxunder fed high fat meal conditions was approximately 74% lower than the Cmaxobserved under fasting conditions. Similarly, mean AUC0-Twas 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.
| Cmax (ng/mL) | Tmax (hrs) | AUC0-T (ng∙hr/mL) | AUC0-Inf (ng∙hr/mL) | T1/2 (hrs) | |
|---|---|---|---|---|---|
Fasting (n=37) | 0.318 ± 0.190 | 3.10 ± 1.08 | 1.74 ± 1.07 | 1.81 ± 1.09 | 3.0 ± 1.2 |
Fed (n=36) | 0.084 ± 0.081 | 2.60 ± 1.12 | 0.38 ± 0.14 | 0.46 ± 0.13n=35 | 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.
The pharmacokinetics of glycopyrrolate by race has not been characterized.
Glycopyrrolate pharmacokinetics have not been characterized in the elderly.
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.
Glycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.
| 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 |
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Cuvposa Prescribing Information
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
See FDA-approved patient labeling (Patient Information)
- Advise patients/caregivers to measure CUVPOSA with an accurate measuring device. A household teaspoon is not an accurate measuring device. Patients/caregivers should use a dosing cup available in pharmacies to accurately measure the correct milliliter dose. An oral syringe, also available in pharmacies, should be used to dispense CUVPOSA into the child's mouth from the cup. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.
- Administering CUVPOSA with a high fat meal substantially reduces the amount of glycopyrrolate absorbed. Administer CUVPOSA at least one hour before or two hours after meals.
- CUVPOSA is started at a low dose and gradually titrated over a period of weeks based on therapeutic response and adverse reactions. Patients/caregivers should not increase the dose without the physician's permission.
- Common adverse reactions from CUVPOSA include overly dry mouth, constipation, vomiting, flushing of the skin or face, and urinary retention. Side effects can sometimes be difficult to detect in some patients with neurologic problems who cannot adequately communicate how they feel. If side effects become troublesome after increasing a dose, decrease the dose to the prior one and contact your physician.
- Constipation is the most common side effect of glycopyrrolate, and if constipation occurs, stop administering glycopyrrolate to the patient and call their healthcare practitioner.
- Inability of the patient to urinate, dry diapers or undergarments, irritability or crying may be signs of urinary retention, and if urinary retention occurs, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner.
- If the patient develops a skin rash, hives or an allergic reaction, patients/caregivers should stop administering glycopyrrolate and call their healthcare practitioner as this could be a sign of hypersensitivity to this product.
- Drugs like glycopyrrolate can reduce sweating, and if the patient is in a hot environment and flushing of the skin occurs this may be due to overheating. Avoid exposure of the patient to hot or very warm environmental temperatures to avoid overheating and the possibility of heat exhaustion or heat stroke.
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
| 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 |
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
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 Cmaxafter oral solution administration was 23% lower compared to tablet administration and AUC0-infwas 28% lower after oral solution administration. Mean Cmaxafter oral solution administration in the fasting state was 0.318 ng/mL, and mean AUC0-24was 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 Cmaxunder fed high fat meal conditions was approximately 74% lower than the Cmaxobserved under fasting conditions. Similarly, mean AUC0-Twas 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.
| Cmax (ng/mL) | Tmax (hrs) | AUC0-T (ng∙hr/mL) | AUC0-Inf (ng∙hr/mL) | T1/2 (hrs) | |
|---|---|---|---|---|---|
Fasting (n=37) | 0.318 ± 0.190 | 3.10 ± 1.08 | 1.74 ± 1.07 | 1.81 ± 1.09 | 3.0 ± 1.2 |
Fed (n=36) | 0.084 ± 0.081 | 2.60 ± 1.12 | 0.38 ± 0.14 | 0.46 ± 0.13n=35 | 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.
The pharmacokinetics of glycopyrrolate by race has not been characterized.
Glycopyrrolate pharmacokinetics have not been characterized in the elderly.
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.
Glycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate have not been evaluated in patients with hepatic impairment.
| 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.
- Pediatric use: The safety and effectiveness of glycopyrrolate has not been established in patients less than 3 years of age. ()
8.4 Pediatric UseCUVPOSA 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.
- Renal impairment: Use CUVPOSA with caution in patients with renal impairment. ()
8.6 Renal ImpairmentBecause glycopyrrolate is largely renally eliminated, CUVPOSA should be used with caution in patients with renal impairment [see
Clinical Pharmacology (12.3)].
CUVPOSA is contraindicated in:
- Patients with medical conditions that preclude anticholinergic therapy (e.g., glaucoma, paralytic ileus, unstable cardiovascular status in acute hemorrhage, severe ulcerative colitis, toxic megacolon complicating ulcerative colitis, myasthenia gravis).
- Patients taking solid oral dosage forms of potassium chloride. The passage of potassium chloride tablets through the gastrointestinal (GI) tract may be arrested or delayed with coadministration of CUVPOSA.
- Constipation or intestinal pseudo-obstruction: May present as abdominal distention, pain, nausea, or vomiting. Assess patients for constipation, particularly within 4-5 days of initial dosing or after a dose increase. ()
5.1 Constipation or Intestinal Pseudo-obstructionConstipation 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. - Incomplete mechanical intestinal obstruction: May present as diarrhea. If obstruction is suspected, discontinue CUVPOSA and evaluate. ()
5.2 Incomplete Mechanical Intestinal ObstructionDiarrhea 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.
- High ambient temperature: To reduce the risk of heat prostration, avoid high temperatures. ()
5.3 High Ambient TemperaturesIn 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.