ZUNVEYL

1 INDICATIONS AND USAGE ZUNVEYL is indicated for the treatment of mild to moderate dementia of the Alzheimer's type in adults. ZUNVEYL is a cholinesterase inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer's type in adults ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended starting dosage is 5 mg orally twice daily with or without food; increase to initial maintenance dosage of 10 mg twice daily after a minimum of 4 weeks based on clinical response and tolerability. Dosage may be increased to the maximum recommended dosage of 15 mg twice a day after a minimum of 4 weeks at 10 mg twice daily. ( 2.1 ) Ensure adequate fluid intake during treatment. Swallow whole; do not split, crush or chew. ( 2.1 ) May be taken with or without food. ( 2.1 ) Should not be taken with alcohol. ( 2.1 ) Hepatic impairment: Should not exceed 10 mg twice daily for moderate hepatic impairment; use in patients with severe hepatic impairment is not recommended ( 2.2 ) Renal impairment: Should not exceed 10 mg twice daily for creatinine clearance 9 to 59 mL/min; use in patients with creatinine clearance less than 9 mL/min is not recommended. ( 2.3 ) 2.1 Recommended Dosage and Administration Dosage The recommended starting dosage is 5 mg twice a day (10 mg/day) by mouth. Increase to initial maintenance dosage of 10 mg twice daily (20 mg/day) after a minimum of 4 weeks, based on clinical response and tolerability. Dosage may be increased to the maximum recommended dosage of 15 mg twice a day (30 mg/day) after a minimum of 4 weeks at 10 mg twice daily. Administration ZUNVEYL can be taken with or without food. ZUNVEYL should not be taken with alcohol [see Clinical Pharmacology (12.3) ]. Swallow whole; do not split, crush or chew. Ensure adequate fluid intake during treatment. Interruption of Therapy If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose. 2.2 Recommended Dosage in Patients with Hepatic Impairment No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh score of 5-6). In patients with moderate hepatic impairment (Child-Pugh score of 7-9), the dosage should generally not exceed 10 mg twice daily (20 mg/day). The use of ZUNVEYL in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended [see Clinical Pharmacology (12.3) ] . 2.3 Recommended Dosage in Patients with Renal Impairment In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 10 mg twice daily (20 mg/day). In patients with creatinine clearance less than 9 mL/min, the use of ZUNVEYL is not recommended [see Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS ZUNVEYL delayed-release tablets are enteric coated and available in the following strengths of benzgalantamine: 5 mg white, round, and convex, debossed with "B05" in grey 10 mg purple, round, and convex, debossed with "B10" in grey 15 mg grey, round, and convex, debossed with "B15" in dark grey Delayed-release tablets: 5 mg, 10 mg, and 15 mg ( 3 )

4 CONTRAINDICATIONS ZUNVEYL is contraindicated in patients with known hypersensitivity to benzgalantamine, galantamine, or to any inactive ingredient in ZUNVEYL. Serious skin reactions have occurred [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]. Known hypersensitivity to benzgalantamine, galantamine, or any inactive ingredients in ZUNVEYL ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail elsewhere in the labeling: Serious Skin Reactions [see Warnings and Precautions (5.1) ] Cardiovascular Conditions [see Warnings and Precautions (5.3) ] Gastrointestinal Conditions [see Warnings and Precautions (5.4) ] Genitourinary Conditions [see Warnings and Precautions (5.5) ] Neurological Conditions [see Warnings and Precautions (5.6) ] Pulmonary Conditions [see Warnings and Precautions (5.7) ] The most common adverse reactions with galantamine tablets (≥5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alpha Cognition Inc. at 1-877-257-4203 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 safety of ZUNVEYL has been established in studies of galantamine immediate-release tablets and galantamine extended-release capsules [see Clinical Studies (14) ] . Below is a display of the adverse reactions of galantamine in these studies. Galantamine Extended-Release Capsules and Immediate-Release Tablets The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 3956 galantamine-treated patients who participated in 8 placebocontrolled clinical studies and 1454 patients in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer's type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with immediate-release galantamine. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials of Galantamine The most common adverse reactions in galantamine-treated patients from double-blind clinical trials (≥5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. Table 1 lists the adverse reactions reported in ≥1% of galantamine-treated patients in 8 placebo-controlled, double-blind clinical trials. Table 1: Adverse Reactions Reported by ≥1% of Galantamine-Treated Patients in 8 Placebo-Controlled, Double-Blind Clinical Trials System/Organ Class Galantamine Placebo Adverse Reaction (n=3956) % (n=2546) % Metabolism and Nutrition Disorders Decreased appetite 7.4 2.1 Psychiatric Disorders Depression 3.6 2.3 Nervous System Disorders Dizziness 7.5 3.4 Headache 7.1 5.5 Tremor 1.6 0.7 Somnolence 1.5 0.8 Syncope 1.4 0.6 Lethargy 1.3 0.4 Cardiac Disorders Bradycardia 1.0 0.3 Gastrointestinal Disorders Nausea 20.7 5.5 Vomiting 10.5 2.3 Diarrhea 7.4 4.9 Abdominal pain 3.8 2.0 Abdominal discomfort 2.1 0.7 Dyspepsia 1.5 1.0 Musculoskeletal and Connective Tissue Disorders Muscle spasms 1.2 0.5 General Disorders and Administration Site Conditions Fatigue 3.5 1.8 Asthenia 2.0 1.5 Malaise 1.1 0.5 Investigations Decreased weight 4.7 1.5 Injury, Poisoning and Procedural Complications Fall 3.9 3.0 Laceration 1.1 0.5 The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5-7 days. Other Adverse Reactions Observed in Clinical Trials of Galantamine The following adverse reactions occurred in <1% of all galantamine-treated patients (N=3956) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in patients (N=1454) who participated in open-label studies. Metabolism and Nutrition Disorders: Dehydration Nervous Sys …

7 DRUG INTERACTIONS Potential to interfere with the activity of anticholinergic medications ( 7.1 ) Synergistic effect expected when given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents, or cholinergic agonists ( 7.2 ) 7.1 Use with Anticholinergics Galantamine has the potential to interfere with the activity of anticholinergic medications. 7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZUNVEYL or galantamine in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically (see Data ). 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data In rats, administration of galantamine (oral doses of 2, 8, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses, which were associated with maternal toxicity. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD) of 22 mg/day galantamine (equivalent to 30 mg/day benzgalantamine) on a body surface area (mg/m 2 ) basis. When galantamine (oral doses of 4, 12, 28, or 40 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose which was associated with maternal toxicity. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD of galantamine on a mg/m2 basis. In a study in which pregnant rats were orally dosed with galantamine (2, 8, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre- and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD of galantamine on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of benzgalantamine or galantamine 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 ZUNVEYL and any potential adverse effects on the breastfed infant from ZUNVEYL or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Eight double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 6519 patients have investigated galantamine in the treatment of mild to moderate dementia of the Alzheimer's type [see Adverse Reactions (6.1) and Clinical Studies (14) ] . The mean age of patients enrolled in these clinical studies was 75 years; 78% of these patients were between 65 and 84 years of age, and 10% of patients were 85 years of age or older. Clinical studies of galantamine did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients. 8.6 Hepatic Impairment In patients with moderate hepatic impairment, a decrease in clearance of galantamine was observed; therefore, a dosage adjustment is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . The use of ZUNVEYL in patients with severe hepatic impairment is not recommended. 8.7 Renal Impairment In patients with a creatinine clearance of 9 to 59 mL/min, an increase in exposure of galantamine was observed; therefore, a dosage adjustment is recommended [see Dosage and Administration (232) and Clinical Pharmacology (12.3) ] . The …

12.1 Mechanism of Action Although the etiology of cognitive impairment in Alzheimer's disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer's disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer's disease). ZUNVEYL is a prodrug of galantamine. Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process.

11 DESCRIPTION ZUNVEYL (benzgalantamine) is a prodrug of galantamine, an acetylcholinesterase inhibitor . Benzgalantamine gluconate is known chemically as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6- benzoate gluconate salt. It has an empirical formula of C 30 H 37 NO 11 and has a molecular weight of 587.61 (gluconate salt) and 391.46 (benzgalantamine). Benzgalantamine gluconate is a white to pale yellow powder and is soluble in water. Benzgalantamine has a pH of 5 to 6 and dissociation constant (pKa) of 7.0. It is slightly soluble in methanol and practically insoluble in acetone, acetonitrile and hexane. The structural formula for benzgalantamine gluconate is: ZUNVEYL contains 5 mg, 10 mg, 15 mg benzgalantamine equivalent to 7.49 mg, 14.98 mg, and 22.47 mg benzgalantamine gluconate, respectively. ZUNVEYL delayed-release tablets are for oral use. Inactive ingredients include calcium silicate, colloidal silicon dioxide, hypromellose, magnesium stearate, mannitol, methacrylic acid, poloxamer 407, polyethylene glycol/macrogol, sodium bicarbonate, sodium lauryl sulfate, sodium stearyl fumarate, talc, and titanium dioxide. The 10 mg tablet also contains Carmine, FD&C Blue #2/Indigo Carmine Aluminum Lake, and FD&C Red #40/Allura Red AC Aluminum Lake. The 15 mg tablet also contains FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Red #40/Allura Red AC Aluminum Lake, and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake. Chemical Structure

10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized. Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the following signs of cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for ZUNVEYL overdosage. Intravenous (IV) atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics. It is not known whether galantamine and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included hypoactivity, tremors, clonic convulsions, salivation, lacrimation, chromodacryorrhea, mucoid feces, and dyspnea. In one postmarketing report, one patient who had been taking 4 mg of galantamine daily for a week inadvertently ingested eight 4 mg tablets (32 mg total) on a single day. Subsequently, she developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness for which she required hospital treatment. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalization. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZUNVEYL delayed-release tablets are enteric coated and supplied in child-resistant packages as follows: 5 mg white tablet debossed with "B05" in grey – bottles of 60 (NDC 84054-005-60) 10 mg purple tablet debossed with "B10" in grey – bottles of 60 (NDC 84054-010-60) 15 mg grey tablet debossed with "B15" in dark grey – bottles of 60 (NDC 84054-015-60) 16.2 Storage and Handling Store ZUNVEYL delayed-release tablets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].