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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serious skin reactions: Discontinue at first appearance of skin rash. ( 5.1 ) All patients should be considered at risk for adverse effects on cardiac conduction, including bradycardia and AV block, because of vagotonic effects on sinoatrial and atrioventricular nodes. ( 5.3 ) Active or occult gastrointestinal bleeding: Monitor, especially those with an increased risk for developing ulcers. ( 5.4 ) Cholinomimetics may cause bladder outflow obstruction. ( 5.5 ) Monitor for respiratory adverse events in patients with a history of severe asthma or obstructive pulmonary disease. ( 5.7 ) 5.1 Serious Skin Reactions Serious skin reactions (e.g., Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving galantamine (the active metabolite of (ZUNVEYL) tablets. Inform patients and caregivers that the use of ZUNVEYL tablets should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed, and alternative therapy should be considered [see Contraindications (4) ]. 5.2 Anesthesia ZUNVEYL, as a cholinesterase inhibitor, is likely to increase the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia. 5.3 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors, including ZUNVEYL, have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients taking cholinesterase inhibitors, both with and without known underlying cardiac conduction abnormalities. Therefore, all patients should be considered at risk for adverse effects on cardiac conduction. 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 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) ] 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 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 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