Galantamine (DB00674): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary & Introduction

Galantamine is a tertiary alkaloid originally isolated from botanical sources, most notably the bulbs and flowers of the common snowdrop, Galanthus nivalis, and other plants belonging to the Amaryllidaceae family.[1] As a parasympathomimetic agent, it is classified pharmacologically as a cholinesterase inhibitor. First characterized in the 1950s by the Bulgarian chemist Dimitar Paskov, galantamine was initially investigated for its effects in paralytic and neuropathic conditions before its therapeutic potential in neurodegenerative disease was fully realized.[1]

The United States Food and Drug Administration (FDA) approved galantamine in 2001, and it is currently indicated for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type.[1] It is available globally as a prescription-only (℞-only) medication under brand names such as Razadyne and Reminyl.[1]

Galantamine is distinguished from other agents in its class by a unique dual mechanism of action. It functions as a reversible, competitive inhibitor of the acetylcholinesterase (AChE) enzyme and, concurrently, as a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors (nAChRs).[1] This dual activity is hypothesized to provide a more robust enhancement of cholinergic neurotransmission, which is known to be deficient in the brains of patients with Alzheimer's disease.

Clinically, galantamine provides modest but statistically significant benefits in improving or slowing the decline of cognitive function, activities of daily living, and behavioral symptoms associated with Alzheimer's disease. It is critical to recognize, however, that like other drugs in its class, galantamine does not alter the underlying progressive course of the neurodegenerative process.[1] Its therapeutic use is characterized by a necessary period of slow dose titration. This careful escalation is essential to manage a prominent profile of dose-dependent gastrointestinal adverse effects, which represents the primary challenge to its tolerability and clinical utility.[2] This monograph provides an exhaustive review of galantamine's chemical properties, pharmacology, pharmacokinetics, clinical efficacy, and safety profile to guide its rational use in clinical practice.

Chemical Identity and Physicochemical Properties

A precise understanding of a drug's chemical and physical nature is fundamental to comprehending its behavior in biological systems. Galantamine's identity is established through a comprehensive set of chemical descriptors and its physicochemical properties dictate its formulation, absorption, and distribution characteristics.

[Nomenclature and Identifiers]

Galantamine is identified by a variety of names and registry numbers across scientific and regulatory domains. These identifiers ensure unambiguous reference to the specific chemical entity.

• Generic Name: Galantamine [1]
• Brand Names: Razadyne, Razadyne ER, Reminyl [1]
• Systematic (IUPAC) Name: (4aS,6R,8aS)-5,6,9,10,11,12-Hexahydro-3-methoxy-11-methyl-4aH-benzofuro[3a,3,2-ef]benzazepin-6-ol [2]
• CAS Number: 357-70-0 (for the free base); 1953-04-4 (for the hydrobromide salt) [2]
• DrugBank ID: DB00674 [1]
• Synonyms and Other Identifiers: Galanthamine, (-)-Galanthamine, Lycoremin, Lycoremine, Nivalin, Jilkon, NSC 100058 [8]

[Chemical Structure and Formula]

Galantamine possesses a complex, rigid tetracyclic structure, which is key to its specific interactions with biological targets.

• Molecular Formula: The empirical formula for the free base is C17​H21​NO3​.[2]
• Molecular Weight: The molar mass of the free base is 287.359 g·mol⁻¹.[2] The clinically used hydrobromide salt ( C17​H21​NO3​⋅HBr) has a molecular weight of 368.27 g·mol⁻¹.[10]
• Structural Classification: Galantamine is classified as a galanthamine-type Amaryllidaceae alkaloid, characterized by a tetracyclic skeleton that includes a benzofuro-azepine core.[3] A key functional group is the tertiary amine within the azepine ring, which is responsible for its basic properties.[2]

[Physicochemical Properties]

The physical and chemical properties of galantamine govern its pharmaceutical formulation and its pharmacokinetic behavior following administration.

• Appearance: Galantamine hydrobromide is a white to almost white, or light yellow, crystalline powder.[10]
• Solubility: The hydrobromide salt is sparingly soluble in water.[10] More specifically, regulatory documents state its solubility in water at a pH of 6.0 is 31 mg/mL.[18] The free base is soluble in organic solvents such as ethanol, acetone, and chloroform but insoluble in benzene and ether.[13]
• Melting Point: Reported melting points for the free base vary, with ranges cited as 119–121 °C and 127–131 °C.[2] The hydrobromide salt has a much higher melting point of 269–270 °C.[20]
• Acidity/Basicity: Galantamine is a weak base, with the tertiary amine of the azepine moiety conferring its basicity. The pKa has been reported as 8.2 [18], with other computational sources estimating the strongest basic pKa in the range of 8.58 to 8.91.[5]
• Lipophilicity: The molecule is slightly lipophilic. This is quantified by its n-octanol/buffer partition coefficient (log P), which was determined to be 1.1 at a pH of 12.0.[18] Other sources report calculated log P values between 1.16 and 1.8.[5] This moderate lipophilicity is sufficient to allow penetration of the blood-brain barrier.
• Biopharmaceutics Classification System (BCS): According to the FDA, galantamine is considered a BCS Class I drug, signifying that it has both high solubility and high permeability.[18]

The designation of galantamine as a BCS Class I drug is a critical determinant of its clinical pharmacology. This classification predicts excellent and consistent absorption from the gastrointestinal tract following oral administration. This prediction is borne out by pharmacokinetic studies demonstrating its high absolute oral bioavailability, which approaches 90-100%.[1] The implication of this property is significant for clinical practice: it suggests that variability in absorption is an unlikely cause for inter-patient differences in response or tolerability. This effectively shifts the focus of pharmacokinetic variability away from the absorption phase and toward downstream processes, namely hepatic metabolism. Consequently, a thorough understanding of its metabolic pathways via the cytochrome P450 system, and the genetic polymorphisms associated with these enzymes, becomes paramount in explaining and predicting differences in drug exposure and, by extension, clinical outcomes and adverse event profiles.

Table 1: Chemical and Physical Properties of Galantamine

Property	Value (Free Base)	Value (Hydrobromide Salt)	Source Snippet(s)
IUPAC Name	(4aS,6R,8aS)-5,6,9,10,11,12-Hexahydro-3-methoxy-11-methyl-4aH-benzofuro[3a,3,2-ef]benzazepin-6-ol	(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef]benzazepin-6-ol hydrobromide	2
CAS Number	357-70-0	1953-04-4	2
Molecular Formula	C17​H21​NO3​	C17​H21​NO3​⋅HBr	2
Molecular Weight	287.359 g·mol⁻¹	368.27 g·mol⁻¹	2
Appearance	White to light yellow crystal	White to almost white powder	10
Melting Point	127.0 to 131.0 °C	269 - 270 °C	15
pKa (Strongest Basic)	8.2 - 8.91	8.58	5
Water Solubility	Insoluble	Sparingly soluble (31 mg/mL at pH 6.0)	13
logP	1.1 - 1.8	1.16	5
BCS Class	Class I (High Solubility, High Permeability)	Not Applicable	18

Pharmacology and Mechanism of Action

Galantamine exerts its therapeutic effects through a distinctive dual mechanism of action that targets the cholinergic system in two complementary ways. It is both a reversible inhibitor of the acetylcholinesterase enzyme and a positive allosteric modulator of nicotinic acetylcholine receptors. This combination is hypothesized to produce a more comprehensive enhancement of cholinergic neurotransmission than could be achieved by either mechanism alone.

[Acetylcholinesterase (AChE) Inhibition]

The primary and most well-understood mechanism of galantamine is its action as a potent, selective, competitive, and reversible inhibitor of acetylcholinesterase.[1] The cholinergic hypothesis of Alzheimer's disease posits that a deficiency in the neurotransmitter acetylcholine (ACh) contributes significantly to the cognitive decline observed in patients. This deficiency arises from the degeneration of acetylcholine-producing neurons in the brain.[10]

Galantamine addresses this deficit by preventing the breakdown of the remaining acetylcholine. It achieves this by binding reversibly to the active site of the AChE enzyme, specifically interacting with the choline-binding site and the acyl-binding pocket. By occupying this site, galantamine competitively blocks the enzyme's access to its natural substrate, acetylcholine. This inhibition of ACh hydrolysis effectively increases the concentration and prolongs the residence time of ACh in the synaptic cleft, thereby enhancing cholinergic signaling at both muscarinic and nicotinic receptors.[1] This is believed to be the principal mechanism underlying its cognitive-enhancing effects.[10]

A key feature of galantamine is its selectivity. It demonstrates significantly greater affinity for AChE compared to butyrylcholinesterase (BuChE), a related enzyme found in plasma and glial cells. Various sources report a selectivity ratio of over 50-fold in favor of AChE.[3] The half-maximal inhibitory concentration (

IC50​) for AChE is reported to be in the range of 0.35 to 0.64 µM, whereas for BuChE, it is approximately 8.4 to 18.6 µM.[3] This selectivity may contribute to its specific pharmacological profile and potentially reduce the incidence of certain peripheral side effects associated with non-selective cholinesterase inhibition.

[Positive Allosteric Modulation (PAM) of Nicotinic Acetylcholine Receptors (nAChRs)]

In addition to its enzymatic inhibition, galantamine possesses a second, unique mechanism of action: it functions as a positive allosteric modulator of nicotinic acetylcholine receptors.[1] Allosteric modulation involves binding to a site on the receptor protein that is topographically distinct from the primary (orthosteric) binding site for the endogenous ligand, in this case, acetylcholine.[2]

By binding to this allosteric site, galantamine induces a conformational change in the nAChR protein. This change does not activate the receptor on its own but rather sensitizes it, increasing the receptor's affinity for acetylcholine and potentiating its response when ACh does bind.[2] This modulatory effect has been demonstrated on several nAChR subtypes relevant to cognition, including the human α4β2, α3β4, α6β4, and α7 subtypes.[2]

The consequences of this modulation are significant. Many nAChRs are located on presynaptic nerve terminals, where they function to regulate the release of various neurotransmitters. By enhancing the activity of these presynaptic nAChRs, galantamine can facilitate the release of not only acetylcholine itself (creating a positive feedback loop) but also other key neurotransmitters involved in cognitive processes, such as glutamate, serotonin, and norepinephrine.[1]

[Synthesis: The Dual Mechanism of Action]

The combination of these two distinct actions—inhibiting the enzyme that degrades ACh and sensitizing the receptors that respond to ACh—constitutes galantamine's signature dual mechanism of action.[1] This synergy is hypothesized to provide a more effective and sustained enhancement of cholinergic function than could be achieved with AChE inhibition alone. The first mechanism increases the supply of the neurotransmitter, while the second amplifies its effect at the receptor level.

Despite the pharmacological elegance of this dual mechanism, which is frequently highlighted as a key differentiator from other Alzheimer's medications, a critical evaluation of the available clinical evidence presents a more nuanced picture. Large-scale meta-analyses and comparative effectiveness studies have consistently failed to demonstrate a clear, statistically significant clinical superiority of galantamine over single-mechanism AChE inhibitors like donepezil in terms of cognitive or functional outcomes.[24] This observation leads to a crucial clinical consideration: the theoretical advantage of the dual-action mechanism does not appear to translate into a measurable efficacy advantage in broad patient populations. This suggests that either the allosteric modulatory effect is not sufficiently potent at clinically achievable concentrations to produce a discernible benefit beyond that of AChE inhibition, or that the primary driver of symptomatic relief for all drugs in this class is the magnitude of the increase in synaptic acetylcholine, rendering the PAM effect clinically marginal. Therefore, while pharmacologically intriguing, the dual mechanism should not be the sole basis for its preferential selection. Instead, clinical decision-making should be guided by more practical factors such as individual patient tolerability, dosing convenience, and cost.

Another important point of comparison arises from galantamine's selectivity. Its high selectivity for AChE over BuChE contrasts sharply with the profile of rivastigmine, which is a non-selective inhibitor of both enzymes.[24] This difference is not merely academic. As Alzheimer's disease progresses, the activity of AChE in the brain may decline, while the activity of BuChE, particularly in glial cells, is thought to increase and play a more substantial role in acetylcholine hydrolysis. This pathological shift implies that a non-selective inhibitor like rivastigmine might offer a broader or more sustained therapeutic effect in the moderate to later stages of the disease. Conversely, galantamine's selectivity may be advantageous in minimizing certain side effects. This mechanistic divergence underscores that the "best" pharmacological profile is context-dependent and may change over the course of the disease, highlighting a potential basis for individualized therapeutic strategies.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of galantamine describes its journey through the body and is essential for determining appropriate dosing regimens, anticipating drug interactions, and understanding inter-patient variability. Its profile is characterized by excellent absorption, moderate distribution, extensive hepatic metabolism with a key pharmacogenomic component, and elimination through multiple pathways.

[Absorption]

Galantamine is rapidly and almost completely absorbed following oral administration, consistent with its BCS Class I designation.

• Bioavailability: The absolute oral bioavailability is very high, ranging from 88.5% to 100%, indicating that nearly the entire oral dose reaches systemic circulation.[1]
• Time to Peak Concentration (Tmax​): For immediate-release (IR) formulations, peak plasma concentrations are reached quickly, at approximately 1 hour post-dose.[1] The development of extended-release (ER) capsules was designed to slow absorption, resulting in a delayed Tmax​ of approximately 4.5 to 5.0 hours.[19]
• Effect of Food: Administration with food has a clinically important effect on the absorption kinetics of the IR formulation. While food does not alter the total amount of drug absorbed (as measured by the area under the curve, or AUC), it significantly blunts the peak concentration (Cmax​) by about 25% and delays the time to reach that peak (Tmax​) by 1.5 hours.[9] This effect is leveraged clinically to improve tolerability, as the common gastrointestinal side effects are often driven by high peak concentrations. For the ER formulation, food has no appreciable effect on its pharmacokinetic parameters.[10]
• Dose Linearity: Galantamine exhibits linear pharmacokinetics, meaning that plasma concentrations increase proportionally with the dose over the clinically relevant range of 8–32 mg/day.[1]

[Distribution]

Once absorbed, galantamine distributes moderately throughout the body, including into its target site, the central nervous system.

• Volume of Distribution (Vd​): The mean volume of distribution is approximately 175 L.[1] This value, being significantly larger than the volume of total body water, indicates that the drug distributes extensively into tissues outside of the plasma.
• Plasma Protein Binding: Galantamine exhibits low binding to plasma proteins, with only 18% of the drug bound at therapeutic concentrations.[1] This low level of protein binding means that it is less susceptible to displacement interactions with other highly protein-bound drugs.
• Blood-Brain Barrier (BBB) Penetration: As required for its central action, galantamine effectively penetrates the blood-brain barrier.[1]
• Blood Cell Distribution: A significant portion of the drug in the blood, about 52.7%, is distributed into red blood cells. This results in a blood-to-plasma concentration ratio of 1.2, meaning concentrations are slightly higher in whole blood than in plasma alone.[1]

[Metabolism]

Galantamine undergoes extensive metabolism, primarily in the liver, which is the main source of inter-individual variability in its pharmacokinetics.

• Primary Metabolic Pathways: Multiple pathways are involved in the elimination of galantamine. Approximately 75% of the drug is metabolized by the cytochrome P450 (CYP) enzyme system, with two isoenzymes playing major roles: CYP2D6 and CYP3A4.[1]
• CYP2D6-Mediated Pathway: This enzyme is responsible for the O-demethylation of galantamine, which produces the metabolite O-desmethyl-galantamine.[1]
• CYP3A4-Mediated Pathway: This enzyme mediates the N-oxidation of the parent drug to form galantamine-N-oxide.[1]
• Other Pathways: In addition to oxidation by CYP enzymes, galantamine also undergoes Phase II metabolism via glucuronidation to form galantamine glucuronide. Other minor pathways include epimerization and N-demethylation.[1] The resulting metabolites, such as epigalantamine, are not considered to have clinically significant pharmacological activity.[9]
• Pharmacogenomics (CYP2D6 Polymorphism): The gene for the CYP2D6 enzyme is highly polymorphic. Approximately 7% of the Caucasian population are "poor metabolizers" (PMs), possessing genetic variants that result in a non-functional or poorly functional enzyme.[27] In these individuals, the primary O-demethylation pathway is impaired, leading to a decrease in galantamine clearance by about 25% and a corresponding increase in drug exposure (AUC) of about 35% compared to "extensive metabolizers" (EMs) with normal enzyme function.[19] Despite this pharmacokinetic difference, the FDA-approved labeling does not recommend routine genetic testing or specific dose adjustments for PMs. The rationale is that the standard clinical practice of individual dose titration based on tolerability is sufficient to account for this variability.[19]

[Excretion]

Galantamine and its metabolites are eliminated from the body through both renal and fecal routes.

• Elimination Half-Life (t1/2​): The terminal elimination half-life of galantamine is consistently reported to be approximately 7 hours.[2] This relatively short half-life necessitates twice-daily administration for the IR formulation to maintain steady-state therapeutic concentrations.
• Routes of Elimination: Following administration of a radiolabeled dose, approximately 95% of the radioactivity is recovered in the urine and about 5% is recovered in the feces over 7 days.[1]
• Clearance: Galantamine is considered a low-clearance drug.[18] The total plasma clearance is approximately 300 mL/min. Of this, renal clearance of the unchanged drug accounts for about 65 mL/min, or 20–25% of the total clearance.[9]
• Urinary Excretion Profile: In the first 24 hours, about 20% of an administered dose is excreted as unchanged galantamine in the urine.[1] The major metabolite found in urine is galantamine glucuronide, which accounts for another 12% of the dose.[10]

The entire clinical strategy for the safe and effective use of galantamine is a direct and logical consequence of this pharmacokinetic profile. The short 7-hour half-life dictates the need for twice-daily dosing of the IR formulation to avoid large fluctuations in plasma concentration and maintain therapeutic effect.[28] The development of the ER formulation was a direct pharmaceutical response to the inconvenience this posed for a patient population with memory impairment. The prominent gastrointestinal side effects, which are often concentration-dependent and linked to the

Cmax​, are managed by recommending administration of the IR form with food, a practice that blunts the peak concentration by 25%.[9] The slow, four-week dose titration schedule allows for physiological adaptation to the rising drug concentrations and cholinergic effects, further enhancing tolerability.[6] Finally, the reliance on CYP2D6/3A4 for metabolism and on renal excretion for clearance directly informs the need for dose limitations in patients with hepatic or renal impairment, or in those taking potent inhibitors of these enzymes, as any reduction in clearance will lead to higher drug exposure and an increased risk of adverse events.[6] A clinician who grasps these fundamental ADME principles can anticipate and effectively manage the majority of challenges associated with galantamine therapy.

Table 2: Summary of Key Pharmacokinetic Parameters for Galantamine

Parameter	Immediate-Release (IR)	Extended-Release (ER)	Source Snippet(s)
Absolute Bioavailability	~90% (88.5-100%)	~90%	1
Tmax​ (Time to Peak)	~1 hour	4.5 - 5.0 hours	1
Effect of Food	AUC unchanged, Cmax​ ↓ 25%, Tmax​ delayed 1.5 h	No appreciable effect	9
Plasma Protein Binding	18%	18%	1
Volume of Distribution (Vd​)	175 L	175 L	1
Elimination Half-Life (t1/2​)	~7 hours	~7 hours	2
Major Metabolic Enzymes	CYP2D6, CYP3A4	CYP2D6, CYP3A4	2
% Excreted Unchanged in Urine (24h)	~20%	~20%	1

Clinical Efficacy and Therapeutic Applications

The clinical utility of galantamine is primarily centered on its FDA-approved indication for Alzheimer's disease, though its cognitive-enhancing properties have prompted investigation into a range of other neurological and psychiatric conditions.

[Management of Mild to Moderate Alzheimer's Disease (FDA-Approved Indication)]

The efficacy of galantamine for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type is well-established through a robust body of evidence from numerous large-scale, randomized, double-blind, placebo-controlled clinical trials and subsequent meta-analyses.[7]

• Cognitive Outcomes: The most consistent and significant benefit is observed in the cognitive domain. A comprehensive 2024 Cochrane systematic review, representing the highest level of evidence, concluded with high certainty that galantamine at therapeutic doses (16–24 mg/day) produces a statistically significant and, importantly, clinically meaningful improvement in cognitive function compared to placebo at six months.[31] This was primarily measured using the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-cog), where treatment with galantamine resulted in an average score improvement of 2.86 points more than placebo.[31] A separate meta-analysis by Wang et al. (2016) reported a similar mean difference of -3.15 points, further corroborating this effect.[7]
• Functional Outcomes: Beyond cognition, galantamine has demonstrated benefits in preserving patients' ability to perform activities of daily living (ADLs). The Cochrane review found that treatment improved scores on the Disability Assessment for Dementia (DAD) scale, indicating a slowing of functional decline.[31]
• Global and Behavioral Outcomes: The overall clinical picture is also positively impacted. Galantamine treatment leads to better global assessment scores, as measured by tools like the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), where patients on galantamine were more likely to be rated as improved compared to those on placebo (Odds Ratio 1.58).[7] Furthermore, it has shown efficacy in managing the behavioral and psychological symptoms of dementia, with improvements noted on the Neuropsychiatric Inventory (NPI).[31]
• Long-Term Efficacy: The benefits of galantamine are not limited to short-term trials. Long-term studies, with durations of up to two years, have shown that galantamine continues to slow the rate of decline in both memory and the ability to perform self-care activities when compared to placebo.[31] However, it is crucial to communicate to patients and caregivers that Alzheimer's is a progressive disease. The therapeutic effect of galantamine is symptomatic and may lessen over time as the underlying pathology advances and the number of functional cholinergic neurons diminishes.[1]

[Investigational and Off-Label Uses]

The pro-cholinergic effects of galantamine have led to its investigation in other conditions characterized by cognitive deficits.

• Mild Cognitive Impairment (MCI): Galantamine was extensively studied for the treatment of MCI, a condition that often precedes Alzheimer's dementia. However, these large-scale trials yielded disappointing results. They demonstrated only marginal, if any, clinical benefit on cognitive outcomes and, more concerningly, revealed an unexplained and statistically significant increase in mortality in the galantamine-treated groups compared to placebo.[1] As a result of these findings, the use of galantamine for the treatment of MCI is not recommended and carries a specific warning in its FDA-approved labeling.[6]
• Cognitive Impairment in Schizophrenia: The cognitive deficits associated with schizophrenia represent a major area of unmet therapeutic need. Completed Phase 4 clinical trials have formally investigated the potential of galantamine as an adjunctive treatment to improve cognitive function in this patient population.[1]
• Attention-Deficit/Hyperactivity Disorder (ADHD): The role of the cholinergic system in attention and executive function has prompted exploration of galantamine in ADHD. At least one completed Phase 4, double-blind, placebo-controlled trial has evaluated its efficacy in adults with ADHD.[37]
• Other Psychiatric Disorders: Early exploratory studies also considered galantamine's potential to ameliorate cognitive symptoms in other disorders, including bipolar disorder and autism, though these have not been pursued to the same extent as its use in Alzheimer's disease.
• Oneirogenic Effects: A novel area of research involves galantamine's purported ability to act as an oneirogen, an agent that induces or enhances dream states. It is currently being studied for its capacity to promote lucid dreaming, a state in which the dreamer is aware they are dreaming. This effect is thought to be mediated by an increase in the duration of REM sleep. Doses of 4 to 12 mg taken during the night are being investigated for this speculative application.[9]

A critical pattern that emerges from a holistic review of the clinical trial data is the inherent tension between efficacy and tolerability. While pivotal trials clearly demonstrate statistically significant benefits, they simultaneously report high rates of adverse events and premature treatment discontinuation. For instance, pooled data show that nearly 23% of patients on galantamine discontinue treatment prematurely, compared to about 17% on placebo, with the difference driven primarily by cholinergic side effects.[35] This suggests that in real-world clinical practice, a substantial proportion of patients may be unable to tolerate the therapeutic doses required to achieve the efficacy observed under controlled trial conditions, thereby limiting the drug's overall effectiveness. Furthermore, the analytical methods used in some older trials, such as the "last observation carried forward" (LOCF) approach, may have introduced a positive bias. This method carries forward the last available data point for patients who drop out, potentially inflating the apparent efficacy of the drug by not capturing the subsequent decline of those who could not tolerate it.[35] This context is vital for clinicians; the "on-paper" efficacy of galantamine must be interpreted with the understanding that achieving it in an individual patient is contingent upon successfully managing the significant side effect burden through meticulous dose titration and patient education.

Dosage, Formulations, and Administration

The successful implementation of galantamine therapy hinges on a thorough understanding of its available formulations, adherence to a strict dose-titration schedule, and appropriate dose adjustments for specific patient populations. The overarching principle is to "start low and go slow" to maximize tolerability.

[Formulations]

Galantamine is available in three oral formulations to accommodate different patient needs:

• Immediate-Release (IR) Tablets: Marketed as Razadyne® tablets, they are available in strengths of 4 mg, 8 mg, and 12 mg.[6] These require twice-daily administration.
• Extended-Release (ER) Capsules: Marketed as Razadyne® ER, these capsules are designed for once-daily dosing and are available in strengths of 8 mg, 16 mg, and 24 mg.[6] The 24 mg ER capsule administered once daily is bioequivalent to the 12 mg IR tablet administered twice daily in terms of total daily exposure (AUC) and minimum concentration ( Cmin​).[9]
• Oral Solution: Available as a 4 mg/mL solution, providing an alternative for patients who have difficulty swallowing tablets or capsules.[6]

[Dosing and Titration]

A gradual dose escalation is mandatory to allow for patient acclimatization to the drug's cholinergic effects and to minimize the incidence and severity of adverse events, particularly gastrointestinal side effects.[6]

• Immediate-Release (IR) Regimen:
• Starting Dose: Therapy should be initiated at a dose of 4 mg administered twice daily, preferably with the morning and evening meals to improve tolerability.[6]
• Titration Schedule: After a minimum of four weeks at the starting dose, the dosage should be increased to the initial maintenance dose of 8 mg twice daily (total of 16 mg/day). After a minimum of another four weeks, a further increase to 12 mg twice daily (total of 24 mg/day) may be attempted, based on an assessment of clinical benefit and tolerability.[6]
• Maintenance Dose: The recommended maintenance dosage range is 16–24 mg/day. While a 32 mg/day dose was studied, it was found to be less well-tolerated without providing significant additional efficacy and is therefore not recommended.[6]
• Extended-Release (ER) Regimen:
• Starting Dose: Therapy is initiated at 8 mg administered once daily in the morning, preferably with food.[6]
• Titration Schedule: After a minimum of four weeks, the dose should be increased to the maintenance dose of 16 mg once daily. If additional benefit is sought and the 16 mg dose is well-tolerated, a further increase to 24 mg once daily can be considered after a minimum of another four weeks.[6]
• Maintenance Dose: The effective maintenance dosage is 16–24 mg/day.[6]
• Important Administrative Considerations:
• Switching Formulations: Patients can be converted from the IR formulation to the ER formulation at the same total daily dose. The recommended procedure is to take the last dose of the IR tablet in the evening and begin the once-daily ER capsule the following morning.[9]
• Treatment Interruption: If therapy is interrupted for more than three days for any reason, it must be re-initiated at the lowest starting dose (4 mg twice daily for IR or 8 mg once daily for ER) and re-titrated according to the standard schedule.[9]
• Fluid Intake: Patients and caregivers should be counseled to ensure adequate fluid intake during treatment to prevent dehydration, which can be exacerbated by gastrointestinal side effects.[9]

[Dosing in Specific Populations]

Dose adjustments are required for patients with impaired organ function due to altered drug clearance.

• Hepatic Impairment:
• Moderate (Child-Pugh score 7–9): Galantamine clearance is reduced by approximately 25% in this population.[18] The total daily dose should generally not exceed 16 mg/day.[6]
• Severe (Child-Pugh score 10–15): The use of galantamine is not recommended due to the expected significant increase in drug exposure and lack of safety data.[6]
• Renal Impairment:
• Moderate (Creatinine Clearance 9–59 mL/min): Renal impairment in this range increases drug exposure (AUC) by approximately 37%.[18] The total daily dose should generally not exceed 16 mg/day.[6]
• Severe (Creatinine Clearance <9 mL/min): Drug exposure is increased by 67%.[18] The use of galantamine is not recommended in this population.[6]
• CYP2D6 Poor Metabolizers: As previously noted, no specific dose adjustment is mandated for this group, as the standard practice of titrating to individual tolerability is considered sufficient to manage the ~25% reduction in clearance.[19]

Table 3: Dosing and Administration Guidelines for Galantamine Formulations

Population/Condition	Immediate-Release (IR) Regimen	Extended-Release (ER) Regimen	Source Snippet(s)
Standard Initial Dose	4 mg twice daily	8 mg once daily	6
Titration Schedule	Increase after ≥4 weeks to 8 mg BID. May increase after another ≥4 weeks to 12 mg BID.	Increase after ≥4 weeks to 16 mg QD. May increase after another ≥4 weeks to 24 mg QD.	6
Maintenance Dose	16 - 24 mg/day (in two divided doses)	16 - 24 mg/day (once daily)	6
Max Recommended Dose	24 mg/day	24 mg/day	6
Moderate Hepatic Impairment	Max dose: 16 mg/day	Max dose: 16 mg/day	6
Severe Hepatic Impairment	Not Recommended	Not Recommended	6
Moderate Renal Impairment	Max dose: 16 mg/day	Max dose: 16 mg/day	6
Severe Renal Impairment	Not Recommended	Not Recommended	6

Safety and Tolerability Profile

The safety profile of galantamine is largely predictable based on its cholinergic mechanism of action. While generally considered safe when used as directed, it is associated with a significant incidence of adverse effects that can limit its use and requires careful monitoring for several potentially serious reactions.

[Adverse Reactions]

The adverse event profile is dominated by gastrointestinal and neurological symptoms.

• Most Common Adverse Reactions (Incidence ≥5%): The most frequently reported side effects are a direct consequence of increased cholinergic stimulation. These include nausea (reported in up to 21% of patients in clinical trials), vomiting, diarrhea, decreased appetite, and subsequent weight loss. Neurological effects such as dizziness and headache are also common.[2]
• Common Reasons for Discontinuation (Incidence ≥1%): The tolerability of galantamine is often the limiting factor in its use. The adverse events most commonly leading to treatment cessation are nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%).[39]
• Less Common but Clinically Significant and Serious Adverse Reactions:
• Cardiovascular Effects: Due to its vagotonic effects (stimulation of the vagus nerve), galantamine can slow cardiac conduction. This can manifest as bradycardia (slow heart rate), sinoatrial (SA) block, and atrioventricular (AV) block, which can lead to syncope (fainting) and falls. Chest pain has also been reported.[2]
• Gastrointestinal Effects: Increased gastric acid secretion is a known cholinergic effect, which can increase the risk of developing peptic ulcers and gastrointestinal bleeding. This risk is elevated in patients with a prior history of ulcer disease or those concurrently using nonsteroidal anti-inflammatory drugs (NSAIDs).[2]
• Dermatologic Reactions: Rare but potentially life-threatening serious skin reactions have been reported. These include Stevens-Johnson Syndrome (SJS), a severe condition involving blistering and peeling of the skin and mucous membranes, and Acute Generalized Exanthematous Pustulosis (AGEP). The FDA label includes a prominent warning to discontinue galantamine at the first appearance of any skin rash and seek immediate medical evaluation.[6]
• Neurological Effects: Cholinomimetic drugs are believed to have the potential to cause generalized convulsions or seizures. While the underlying disease may also increase seizure risk, galantamine may contribute to this risk.[6]
• Genitourinary Effects: Cholinergic stimulation can increase smooth muscle tone in the urinary tract, potentially causing or exacerbating bladder outflow obstruction, leading to difficulty urinating.[6]
• Pulmonary Effects: Increased bronchial secretions and bronchoconstriction are potential cholinergic effects. Therefore, galantamine should be used with caution in patients with a history of severe asthma or chronic obstructive pulmonary disease (COPD), as it may exacerbate these conditions.[6]

[Contraindications, Warnings, and Precautions]

The use of galantamine is governed by specific contraindications and a set of warnings and precautions issued by regulatory authorities like the FDA.

• Contraindications: The only absolute contraindication is a known hypersensitivity to galantamine hydrobromide or any of the excipients used in the pharmaceutical formulation.[6]
• Major Warnings and Precautions (from FDA Labeling):
• Serious Skin Reactions: As noted above, discontinue immediately at the first sign of a rash.[6]
• Cardiovascular Conditions: All patients should be considered at risk for adverse effects on cardiac conduction. Use with caution and monitor closely, especially in patients with pre-existing conditions like "sick sinus syndrome" or other supraventricular conduction abnormalities, or those taking concomitant medications that slow the heart rate.[6]
• Gastrointestinal Conditions: Monitor all patients for symptoms of active or occult gastrointestinal bleeding (e.g., black, tarry stools; "coffee-ground" vomit), particularly those at high risk.[6]
• Anesthesia: As a cholinesterase inhibitor, galantamine is expected to exaggerate the muscle-relaxant effects of succinylcholine and similar neuromuscular blocking agents used during anesthesia. The anesthesiologist should be informed that the patient is taking galantamine.[6]
• Pulmonary Conditions: Prescribe with caution for patients with a history of severe asthma or COPD.[6]
• Neurological Conditions: Monitor for seizures, as cholinomimetics may lower the seizure threshold.[6]
• Genitourinary Conditions: Use with caution in patients with a history of bladder outflow obstruction.[6]
• Deaths in Subjects with Mild Cognitive Impairment (MCI): Clinical trials in patients with MCI found an unexplained higher mortality rate in patients treated with galantamine compared to placebo. Galantamine is not indicated for the treatment of MCI.[6]

Clinically Significant Drug Interactions

The potential for drug-drug interactions with galantamine is significant and stems from both its pharmacodynamic (effects on the cholinergic system) and pharmacokinetic (metabolism by CYP enzymes) properties.

[Pharmacodynamic Interactions]

These interactions occur when two drugs have additive or opposing effects on the same physiological systems.

• Other Cholinergic Agents: Co-administration of galantamine with other cholinesterase inhibitors (e.g., donepezil, rivastigmine) or direct-acting cholinomimetic drugs (e.g., bethanechol) is expected to result in synergistic cholinergic effects. This would significantly increase the risk of adverse reactions such as severe nausea, vomiting, bradycardia, and salivation, and is therefore not a recommended combination.[44] Similarly, galantamine can prolong the neuromuscular blockade caused by depolarizing muscle relaxants like succinylcholine.[6]
• Anticholinergic Agents: Galantamine and anticholinergic medications have opposing mechanisms of action. Galantamine increases acetylcholine levels, while anticholinergics (e.g., atropine, oxybutynin, aclidinium, tricyclic antidepressants) block acetylcholine receptors. Concomitant use can lead to a mutual antagonism, where galantamine may reduce the efficacy of the anticholinergic drug, and the anticholinergic drug may blunt the therapeutic effect of galantamine. This combination should be used with caution and close monitoring.[14]
• Bradycardia-Inducing Drugs: Galantamine has a vagotonic effect that slows heart rate. When co-administered with other drugs that also decrease heart rate or AV nodal conduction, such as beta-blockers (e.g., metoprolol, atenolol), non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem), digoxin, or amiodarone, there is an increased risk of clinically significant bradycardia and heart block. Careful monitoring of heart rate and rhythm is essential, and consultation with a cardiologist may be warranted before initiating therapy in patients on these agents.[14]

[Pharmacokinetic Interactions]

These interactions occur when one drug alters the absorption, distribution, metabolism, or excretion of another. For galantamine, the most important interactions involve its metabolism.

• Inhibitors of CYP2D6 and CYP3A4:
• Mechanism: Galantamine is primarily metabolized by CYP2D6 and CYP3A4. Concomitant administration of drugs that are strong inhibitors of these enzymes will decrease galantamine's clearance, leading to increased plasma concentrations and a higher risk of cholinergic adverse effects.[2]
• Examples and Management:
• Strong CYP2D6 Inhibitors: Drugs such as quinidine, paroxetine, and fluoxetine can significantly increase galantamine exposure. Population pharmacokinetic analyses showed that these drugs decreased galantamine clearance by 25–33%.[10]
• Strong CYP3A4 Inhibitors: Drugs such as ketoconazole, itraconazole, ritonavir, and erythromycin can also increase galantamine levels.[44]
• Clinical Approach: When initiating treatment with a strong inhibitor of either CYP2D6 or CYP3A4 in a patient already taking galantamine, the patient should be monitored closely for adverse reactions, and a dose reduction of galantamine may be necessary.
• Inducers of CYP2D6 and CYP3A4:
• Mechanism: Strong inducers of these enzymes (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) can increase the metabolism of galantamine, leading to lower plasma concentrations and potentially reduced therapeutic efficacy. Dose adjustments of galantamine may be needed if an inducer is started or stopped.
• Effect of Galantamine on Other Drugs: In vitro studies indicate that galantamine itself has a very low potential to inhibit the major CYP450 isoenzymes (CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6, and CYP2E1) at clinically relevant concentrations. Therefore, it is considered unlikely to significantly alter the metabolism of other drugs that are substrates for these enzymes.[10]

Comparative Analysis and Clinical Context

Positioning galantamine within the therapeutic landscape for Alzheimer's disease requires a comparative analysis against other available treatments, primarily the other acetylcholinesterase inhibitors (donepezil, rivastigmine) and the NMDA receptor antagonist (memantine). The choice among these agents is rarely based on superior efficacy but rather on a nuanced evaluation of tolerability, convenience, and individual patient characteristics.

[Comparison with Other Acetylcholinesterase Inhibitors (Donepezil, Rivastigmine)]

• Efficacy: The overwhelming consensus from head-to-head clinical trials, systematic reviews, and indirect meta-analyses is that there are no consistent, statistically significant differences in overall efficacy among galantamine, donepezil, and rivastigmine on major cognitive and functional outcomes.[24] While some individual studies have reported numerical trends favoring one drug over another on a specific assessment scale (e.g., one open-label study suggested a trend of rivastigmine > donepezil > galantamine on the ADAS-cog), these findings have not been consistently replicated and are often from studies with methodological limitations.[24] The clinical benefit derived from all three agents is considered to be of a similar, modest magnitude.
• Tolerability and Safety: This is where the drugs begin to differentiate. Multiple analyses have shown that donepezil generally has a more favorable tolerability profile. It is associated with lower rates of gastrointestinal side effects, particularly nausea and vomiting, and lower rates of treatment discontinuation due to adverse events when compared to both galantamine and rivastigmine.[24]
• Dosing and Adherence: Donepezil's simple once-daily dosing schedule has historically offered a significant advantage in convenience, which is particularly important in a patient population with cognitive impairment. This has been linked to better treatment adherence and higher caregiver satisfaction.[24] The development of the extended-release (ER) formulation of galantamine and the transdermal patch for rivastigmine were direct pharmaceutical innovations aimed at leveling this playing field by offering once-daily administration options.
• Mechanistic Differences: As previously discussed, a key theoretical difference is rivastigmine's dual inhibition of both AChE and BuChE. This contrasts with the more selective AChE inhibition of donepezil and galantamine (with galantamine's additional nAChR modulation). The potential for BuChE inhibition to become more relevant as Alzheimer's disease progresses remains a point of pharmacological debate but has not translated into proven, superior long-term efficacy for rivastigmine in clinical trials.[24]

[Comparison with Memantine (NMDA Receptor Antagonist)]

• Mechanism and Indication: Memantine operates through an entirely different mechanism, acting as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. It is approved for the treatment of moderate-to-severe Alzheimer's disease, a later stage than the primary indication for AChEIs.[45]
• Efficacy: A Bayesian meta-analysis that compared multiple Alzheimer's drugs suggested that memantine might have a greater beneficial effect on the Mini-Mental State Examination (MMSE) score compared to the AChEIs, including galantamine.[24]
• Combination Therapy: Given their complementary mechanisms of action, AChEIs and memantine are often used in combination, particularly as a patient's disease progresses from the mild to the moderate stage. A clinical trial has specifically evaluated the efficacy and safety of the galantamine-memantine combination regimen.[30]

The collective evidence strongly suggests that the clinical positioning of galantamine and the choice among the AChEIs should be driven less by claims of superior efficacy and more by a pragmatic assessment of individual patient factors. Donepezil is often considered a first-line choice due to its established efficacy combined with a generally superior tolerability profile and the simplicity of its once-daily dosing. Galantamine, particularly in its ER formulation, stands as a valid and competitive alternative. The decision to use galantamine might be influenced by local formulary availability, cost, or as a second-line option in a patient who does not tolerate or respond adequately to donepezil. Indeed, some evidence suggests that switching from an ineffective or poorly tolerated AChEI to another, such as from donepezil to galantamine, may be beneficial for some patients.[9] The unique dual mechanism of galantamine, while pharmacologically interesting, should not be the primary determinant of its selection, given the absence of clear evidence that it confers a consistent clinical advantage over its competitors. The "best" drug is ultimately the one that an individual patient can tolerate at an effective dose for a sustained period.

Table 4: Comparative Profile of Galantamine vs. Other Alzheimer's Medications

Feature	Galantamine	Donepezil	Rivastigmine	Memantine
Mechanism of Action	Reversible AChE inhibitor; nAChR positive allosteric modulator	Reversible, selective AChE inhibitor	Pseudo-irreversible inhibitor of AChE and BuChE	Non-competitive NMDA receptor antagonist
FDA Indication	Mild to Moderate AD	Mild, Moderate, & Severe AD	Mild, Moderate, & Severe AD	Moderate to Severe AD
Dosing Frequency	Twice daily (IR); Once daily (ER)	Once daily	Twice daily (oral); Once daily (patch)	Once or twice daily
Key Efficacy Findings	Modest benefit in cognition, function, behavior. Efficacy comparable to other AChEIs.	Modest benefit in cognition, function, behavior. Efficacy comparable to other AChEIs.	Modest benefit in cognition, function, behavior. Efficacy comparable to other AChEIs.	Modest benefit, primarily in moderate-to-severe AD. Often used in combination.
Primary Adverse Effects	Nausea, vomiting, diarrhea, dizziness, bradycardia	Nausea, diarrhea, insomnia, vomiting, bradycardia	Nausea, vomiting, diarrhea, anorexia, dizziness, bradycardia	Dizziness, headache, confusion, constipation
Key Clinical Advantage	Dual mechanism (theoretical); ER formulation available	Generally best-tolerated AChEI; simple once-daily dosing	Transdermal patch bypasses GI tract, improving GI tolerability; BuChE inhibition (theoretical)	Different mechanism allows for combination therapy with AChEIs
Key Clinical Disadvantage	High incidence of GI side effects; requires slow titration	Less effective in some patients; potential for sleep disturbances	Highest incidence of GI side effects with oral form; requires slow titration	Efficacy primarily in later stages; can cause confusion
Source Snippet(s)	1	24	24	24

Conclusion and Expert Recommendations

Galantamine is a well-established medication for the symptomatic management of mild to moderate dementia of the Alzheimer's type. Its profile is defined by a unique dual mechanism of action, involving both acetylcholinesterase inhibition and positive allosteric modulation of nicotinic receptors. While this dual action is pharmacologically distinct, the totality of clinical evidence indicates that its efficacy in improving cognition and function is of a modest magnitude and broadly comparable to that of other acetylcholinesterase inhibitors.

The primary challenge and key determinant of success in galantamine therapy is its tolerability. The prominent, dose-dependent gastrointestinal adverse effects—nausea, vomiting, and diarrhea—necessitate a careful and patient approach to treatment initiation and dose escalation. The availability of an extended-release formulation offers a valuable tool to potentially improve tolerability and enhance patient adherence.

Based on a comprehensive analysis of the available data, the following recommendations are provided for clinicians:

• Patient Selection: Galantamine is an appropriate therapeutic option for patients with a confirmed diagnosis of mild to moderate Alzheimer's disease. It is not indicated and should not be used for the treatment of Mild Cognitive Impairment (MCI) due to a lack of benefit and an observed increase in mortality in clinical trials. Extreme caution should be exercised, or the drug avoided, in patients with significant underlying cardiac conduction disease (e.g., sick sinus syndrome, AV block), a high-risk profile for gastrointestinal bleeding (e.g., active peptic ulcer disease, concurrent high-dose NSAID use), or severe renal (CrCl<9mL/min) or hepatic (Child-Pugh > 9) impairment.
• Dose Optimization and Administration: Strict adherence to the recommended slow dose-titration schedule, with dose increases occurring no more frequently than every four weeks, is paramount to minimizing adverse events and achieving a therapeutic dose. The extended-release formulation should be considered to simplify the dosing regimen to once daily, which may improve adherence. Patients and caregivers must be counseled on the importance of administering the medication with food (for IR tablets) and ensuring adequate hydration.
• Monitoring and Management of Adverse Effects: Proactive patient education regarding the high likelihood of transient gastrointestinal side effects is critical for managing expectations and preventing premature discontinuation. Clinicians should monitor patients' weight, heart rate, and for any signs or symptoms of syncope or gastrointestinal bleeding throughout the course of treatment. At the first appearance of a skin rash, galantamine must be discontinued immediately and the patient evaluated for a serious dermatologic reaction.
• Clinical Positioning and Therapeutic Strategy: Galantamine is a valid first-line or second-line choice among the acetylcholinesterase inhibitors. The decision to use it over other agents like donepezil or rivastigmine should be guided by a holistic assessment of individual patient factors, including tolerability profile, potential for drug interactions (particularly with inhibitors or inducers of CYP2D6 and CYP3A4), and formulary or cost considerations. The theoretical "dual mechanism" advantage should not be the primary driver of this decision, as it has not been substantiated by superior clinical efficacy in comparative trials.
• Future Research Directions: The unique pharmacological profile of galantamine suggests several avenues for future investigation. Further research into its off-label applications, such as for cognitive impairment in schizophrenia, is warranted. The exploration of its oneirogenic properties is a novel area of interest. From a drug development perspective, the galantamine scaffold could serve as a template for designing novel compounds with more potent nAChR modulatory effects or improved tolerability. Finally, emerging research into its potential role in modulating neuroinflammation and metabolic dysfunction may open new therapeutic possibilities beyond its current use as a symptomatic treatment for Alzheimer's disease.[9]

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