Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]).
5.4 Gastrointestinal Conditions
Through their primary action, cholinomimetics, including ZUNVEYL, may be expected to increase gastric acid secretion because of increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers (e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs [NSAIDs]). Clinical
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studies of galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss [see Adverse Reactions (6.1)]. Monitor the patient’s weight during therapy with ZUNVEYL.
5.5 Genitourinary Conditions
Although this was not observed in clinical trials with galantamine, cholinomimetics, including ZUNVEYL, may cause bladder outflow obstruction.
5.6 Neurological Conditions
Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions [see Adverse Reactions (6.2)]. Seizure activity may also be a manifestation of Alzheimer’s disease. Patients with Alzheimer’s disease should be monitored closely for seizures while taking ZUNVEYL.
5.7 Pulmonary Conditions
Because of its cholinomimetic action, ZUNVEYL should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease. Respiratory function should be monitored closely for the occurrence of respiratory adverse reactions.
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)]
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.
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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 placebocontrolled, 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 ClassAdverse Reaction | Galantamine(n=3956)% | Placebo(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 |
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| System/Organ ClassAdverse Reaction | Galantamine(n=3956)% | Placebo(n=2546)% |
|---|
| 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 System Disorders: Dysgeusia, Hypersomnia, Paresthesia
Eye Disorders: Blurred vision
Cardiac Disorders: First degree atrioventricular block, Palpitations, Sinus bradycardia, Supraventricular extrasystoles
Vascular Disorders: Flushing, Hypotension
Gastrointestinal Disorders: Retching
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis
Musculoskeletal and Connective Tissue Disorders: Muscular weakness
Discontinuations Due to Adverse Reactions in Clinical Trials of Galantamine
In the 8 placebo-controlled studies of adults, 418 (10.6%) galantamine-treated patients (N=3956) and 56 (2.2%) placebo patients (N=2546) discontinued because of an adverse reaction. Those
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reactions with an incidence of ≥0.5% in the galantamine-treated patients included nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), dizziness (1.3%), diarrhea (0.8%), headache (0.7%), and decreased weight (0.7%). The only event that caused discontinuation with an incidence of ≥0.5% in placebo patients was nausea (17, 0.7%).
In the 5 open-label studies, 103 (7.1%) patients (N=1454) discontinued because of an adverse reaction. Those reactions that caused discontinuation with an incidence of ≥0.5% included nausea (3.0%), vomiting (1.6%), decreased appetite (0.9%), headache (0.8%), decreased weight (0.6%), dizziness (0.6%), and diarrhea (0.5%).
6.2 Postmarketing Experience
The following additional adverse reactions have been identified during postapproval use of galantamine. 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:
Immune System Disorders: Hypersensitivity [see Contraindications (4)]
Psychiatric Disorders: Hallucinations
Nervous System Disorders: Seizures, extrapyramidal disorder [see Warnings and Precautions (5.6)]
Ear and Labyrinth Disorders: Tinnitus
Cardiac Disorders: Complete atrioventricular block
Vascular Disorders: Hypertension
Hepatobiliary Disorders: Hepatitis, increased hepatic enzyme
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, acute generalized exanthematous pustulosis [see Warnings and Precautions (5.1)], erythema multiforme
7 DRUG INTERACTIONS
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.
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8 USE IN SPECIFIC POPULATIONS
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/m2) 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/m2 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.
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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 use of ZUNVEYL in patients with creatinine clearance less than 9 mL/min is not recommended.
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.
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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.
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 C30H37NO11 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.
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12 CLINICAL PHARMACOLOGY
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.
12.2 Pharmacodynamics
There are no relevant pharmacodynamic (PD) data, and the PD effects are unknown for ZUNVEYL.
12.3 Pharmacokinetics
Benzgalantamine is a prodrug of galantamine, the active metabolite. The systemic exposures of benzgalantamine are less than 1% of galantamine exposures; therefore, the pharmacokinetic information presented below is for that of galantamine. Dose-proportionality is observed for ZUNVEYL over the dose range of 5 to 15 mg and steady state is achieved within a week.
Absorption
Galantamine is absorbed with time to peak concentration of about 2.5 to 3 hours. The absolute bioavailability of galantamine is about 90%.
Effect of Food
Food did not affect the Cmax or AUC of galantamine, but Tmax was 6 hours, when ZUNVEYL was administered with food.
Distribution
The mean volume of distribution of galantamine is 175 L. The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.
Elimination
Galantamine is eliminated by hepatic cytochrome P450 enzymes, glucuronidation, and excretion of unchanged drug in the urine.
After IV or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20-25% of the
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total plasma clearance of about 300 mL/min. Galantamine has a terminal half-life of about 7 hours.
Metabolism
Based on in vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of galantamine. CYP2D6 was involved in the formation of O-desmethylgalantamine, whereas CYP3A4 mediated the formation of galantamine-N-oxide. Galantamine is also glucuronidated and excreted unchanged in urine.
Excretion
In studies of oral 3H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93-99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.
Specific Populations
Elderly
Data from clinical trials in patients with Alzheimer’s disease indicate that galantamine concentrations are 30-40% higher in those patients than in healthy young subjects.
Gender and Race
A population pharmacokinetic analysis (on 539 men and 550 women) indicates that galantamine clearance is about 20% lower in women than in men (which is explained by a lower body weight in women) and that race (n=1029 White, 24 Black, 13 Asian, and 23 other) did not affect the clearance of galantamine.
Hepatic Impairment
Following a single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n=8; Child-Pugh score of 5-6) were similar to the pharmacokinetics of galantamine in healthy subjects. In patients with moderate hepatic impairment (n=8; Child Pugh score of 7-9), galantamine clearance was decreased by about 25% compared to galantamine clearance in normal volunteers. Exposure to galantamine would be expected to increase further with increasing degree of hepatic impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].
Renal Impairment
Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in patients with moderate and severe renal impairment, respectively, compared with normal volunteers [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)].
CYP2D6 Pharmacogenetics
No clinically significant differences in the pharmacokinetics of galantamine were observed based on CYP2D6 metabolizer status.
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Drug-Drug Interactions
In Vitro Studies
