Cuvposa

1 INDICATIONS AND USAGE 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 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 )

2 DOSAGE AND ADMINISTRATION 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) ]. Table 1: Recommended Dose Titration Schedule (each dose to be given three times daily) 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 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 reactions. ( 2 ) Maximum recommended dose is 0.1 mg/kg three times daily, not to exceed 1.5-3 mg per dose based upon weight. ( 2 ) Administer at least one hour before or two hours after meals. ( 2 )

4 CONTRAINDICATIONS 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. Medical conditions that preclude anticholinergic therapy. ( 4 ) Concomitant use of solid oral dosage forms of potassium chloride. ( 4 )

5 WARNINGS AND PRECAUTIONS 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 ) Incomplete mechanical intestinal obstruction: May present as diarrhea. If obstruction is suspected, discontinue CUVPOSA and evaluate. ( 5.2 ) High ambient temperature: To reduce the risk of heat prostration, avoid high temperatures. ( 5.3 ) 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

7 DRUG INTERACTIONS Digoxin tablets: Use with glycopyrrolate can increase digoxin serum levels. Monitor patients and consider use of alternative dosage forms of digoxin. ( 7 ) Amantadine: Effects of glycopyrrolate may be increased with concomitant administration of amantadine. Consider decreasing the dose of glycopyrrolate during concomitant use. ( 7 ) Atenolol or metformin: Glycopyrrolate may increase serum levels of atenolol or metformin. Consider dose reduction when used with glycopyrrolate. ( 7 ) Haloperidol or levodopa: Glycopyrrolate may decrease serum levels of haloperidol or levodopa. Consider a dose increase when used with glycopyrrolate. ( 7 ) 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.

6 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. 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 1-844-469-6379 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 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 CUVPOSA (N=20) n (%) Placebo (N=18) n (%) 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. 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 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.

8.1 Pregnancy 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.