Highlights of prescribing information

High ambient temperature: To reduce risk of heat prostration, avoid These highlights do not include all the information needed to use
CUVPOSA safely and effectively. See full prescribing information for
--------------------------ADVERSE REACTIONS-----------------------------------
The most common adverse reactions (incidence ≥30%) are dry mouth, CUVPOSA (glycopyrrolate) oral solution
vomiting, constipation, flushing, and nasal congestion. (6) Initial U.S. Approval: 1961
To report SUSPECTED ADVERSE REACTIONS, contact Shionogi
Drug Safety Department at 1-800-849-9707 ext. 1454 or FDA at

---------------------INDICATIONS AND USAGE----------------------
1-800-FDA-1088 o
CUVPOSA is an anticholinergic indicated to reduce chronic severe drooling in patients aged 3-16 with neurologic conditions associated with problem ---------------------------DRUG INTERACTIONS---------------------------
Digoxin tablets: Use with glycopyrrolate can increase digoxin serum -----------------DOSAGE AND ADMINISTRATION-----------------
levels. Monitor patients and consider use of alternative dosage forms of Initiate dosing at 0.02 mg/kg three times daily and titrate in increments of 0.02 mg/kg every 5-7 days, based on therapeutic response and adverse Amantadine: Effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the Maximum recommended dose is 0.1 mg/kg three times daily, not to dose of glycoypyrrolate during concomitant use. (7) exceed 1.5-3 mg per dose based upon weight. (2) Atenolol or metformin: Glycopyrrolate may increase serum levels of Administer at least one hour before or two hours after meals. (2) atenolol or metformin. Consider dose reduction when used with glycopyrrolate. (7) Haloperidol or levodopa: Glycopyrrolate may decrease serum levels of ----------------DOSAGE FORMS AND STRENGTHS-------------
haloperidol or levodopa. Consider a dose increase when used with 1 mg/5 mL, oral solution in 16 ounce bottles. (3) ---------------------USE IN SPECIFIC POPULATIONS--------------------
Pediatric use: The safety and effectiveness of glycopyrrolate has not Medical conditions that preclude anticholinergic therapy. (4) been established in patients under 3 years of age. (8.4) Concomitant use of solid oral dosage forms of potassium chloride. (4) Renal Impairment: Use CUVPOSA with caution in patients with renal impairment. (8.6) -------------------WARNINGS AND PRECAUTIONS----------------------------
Constipation or intestinal pseudo-obstruction: May present as approved patient labeling
abdominal distention, pain, nausea, or vomiting. Assess patients for constipation, particularly within 4-5 days of initial dosing or after a dose Incomplete mechanical intestinal obstruction: May present as diarrhea. Revised: 07/2010
If obstruction is suspected, discontinue CUVPOSA and evaluate. (5.2) FULL PRESCRIBING INFORMATION: CONTENTS*
5.1 Constipation or Gastrointestinal Pseudo-obstruction 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES
* Sections or subsections omitted from the full 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
CUVPOSA must be measured and administered with 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 consistent 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)].
Table 1: Recommended Dose Titration Schedule (each dose to be given three times daily)

Dose Level 1
Dose Level 2
Dose Level 3
Dose Level 4
Dose Level 5
(~0.02 mg/kg)
(~0.04 mg/kg)
(~0.06 mg/kg)
(~0.08 mg/kg)
(~0.1 mg/kg)
CUVPOSA is available as a 1 mg/5 mL clear, cherry-flavored solution for oral administration in 16 ounce bottles.
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. WARNINGS AND PRECAUTIONS
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 use of anticholinergic drugs such as
CUVPOSA. Advise parents/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:

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. Coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, and hypertension Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition ADVERSE REACTIONS
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. 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. The data described below reflect exposure to CUVPOSA in 151 subjects, including 20 subjects who participated in a 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 Infections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract infection 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 6.2 Postmarketing Experience
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. DRUG INTERACTIONS
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 levels 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. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted with glycopyrrolate. It is also not
known whether glycopyrrolate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CUVPOSA should be given to a pregnant woman only if clearly needed.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CUVPOSA is

8.4 Pediatric Use
CUVPOSA was evaluated for chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling. CUVPOSA has
not been studied in subjects under the age of 3 years.
8.5 Geriatric Use
Clinical studies of CUVPOSA did not include subjects aged 65 and over.
8.6 Renal Impairment
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: • Maintaining an open airway, providing ventilation as necessary. Managing any acute conditions such as hyperthermia, coma and or seizures as applicable, and managing any jerky myoclonic movements or choreoathetosis which may lead to rhabdomyolysis in some cases of anticholinergic overdosage. Administering a quaternary ammonium anticholinesterase such as neostigmine to help alleviate peripheral anticholinergic effects such as anticholinergic induced ileus. Administering activated charcoal orally as appropriate. DESCRIPTION
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.
12.1 Mechanism of Action
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.
12.2 Pharmacodynamics
Glycopyrrolate inhibits the action of acetylcholine on salivary glands thereby reducing the extent of salivation.
12.3 Pharmacokinetics
In a parallel study of children (n=6 per group) aged 7-14 years undergoing intraocular surgery receiving either intravenous (IV) or oral glycopyrrolate as a
premedication, the mean absolute bioavailability of 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 the 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. Table 3: Pharmacokinetic Parameters (mean±SD) for CUVPOSA, Fasting and Fed, in Healthy Adults

Distribution 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). Metabolism 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. Elimination 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. Pediatrics 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 7L/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. Gender Population pharmacokinetic evaluation of adults and children administered IV or oral glycopyrrolate identified no effect of gender on glycopyrrolate clearance or Race The pharmacokinetics of glycopyrrolate by race has not been characterized. Elderly Glycopyrrolate pharmacokinetics have not been characterized in the elderly. Renal Impairment 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. Hepatic Impairment Glycopyrrolate is largely renally eliminated. The pharmacokinetics of glycopyrrolate has not been evaluated in patients with hepatic impairment. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of glycopyrrolate.
Glycopyrrolate did not elicit any genotoxic effects in the Ames mutagenicity assay, the human lymphocyte chromosome aberration assay, or the micronucleus
Glycopyrrolate has not been evaluated for potential to impair fertility. CLINICAL STUDIES
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 given 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 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 mean mTDS values from baseline through Week 8.
Table 4: Percentage of Responders at Week 8

Placebo Group

Figure 1. Mean (± 2 Standard Errors) mTDS Scores


NDC 59630-206-16: 1 mg/5 mL clear, cherry-flavored solution; 16 oz. bottle. Store at room temperature 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature].

See FDA-Approved Patient Labeling.

Advise parent/caregivers to measure CUVPOSA with an accurate measuring device. A household teaspoon is not an accurate measuring device. Parents/caregivers should use a dosing cup available in pharmacies to accurately measure the correct milliliter dose for the patient. 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. Parents/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 a 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, parents/caregivers should stop administering glycopyrrolate and call their healthcare practitioner. If the patient develops a skin rash, hives or an allergic reaction, parents/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. Parents/caregivers should be advised to avoid exposure of the patient to hot or very warm environmental temperatures to avoid overheating and the possibility of heat exhaustion or heat stroke.
Manufactured by:
Mikart, Inc.
Atlanta, GA 30318
Manufactured for:
and non-prescription medicines, vitamins, INFORMATION
CUVPOSA (glycopyrrolate) Oral Solution
How should I give 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 What is CUVPOSA?
in children with medical conditions that Who should not take CUVPOSA?
• has a bowel problem called paralytic oral syringe to give the child each dose • has severe ulcerative colitis or certain cup. Oral syringes are also available at What should I tell the doctor before
giving CUVPOSA to my child?
to control drooling may be different for increase in dose continues until the best dose for your child is reached, to control • has heart problems or abnormal heart • During this time it is important to stay in close contact with your child’s doctor, and tell the doctor about any side effects that your child has. See “What are the What should I avoid while taking
• is breastfeeding or plans to breastfeed. operate heavy machinery, or do other dangerous activities while taking breast milk and if it can harm the baby. Tell your doctor about all the medicines
that your child takes, including prescription
What are the possible side effects of
away. These are not all the possible side CUVPOSA?
Call your doctor for medical advice about • Constipation. Constipation is common
side effects. You may report side effects to How should I store CUVPOSA?
Keep CUVPOSA out of the reach of
Diarrhea and intestinal blockage.
General information about CUVPOSA:
purposes other than those listed in a Patient colostomy or ileostomy. Tell your doctor prescribed. Do not give CUVPOSA to other people even if they have the same condition. • Problems with control of body
temperature (overheating or heat
stroke). CUVPOSA can cause your
This leaflet summarizes the most important like more information, talk with your doctor. stroke if they are in an area that is very You can ask your doctor or pharmacist for information about CUVPOSA that is written What are the ingredients in CUVPOSA?
Inactive Ingredients: citric acid glycerin, citrate, sorbitol solution, and purified water • upper respiratory tract infection • Tell your doctor if your child has any side effect that concerns you or that does not go

Source: ftp://66-192-170-77.static.twtelecom.net/Cuvposa_FULL_label.pdf

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