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Galantamine

Pronunciation

Pronunciation

(ga LAN ta meen)

Index Terms

  • Galantamine Hydrobromide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrobromide [strength expressed as base]:

Razadyne ER: 8 mg, 16 mg, 24 mg

Generic: 8 mg, 16 mg, 24 mg

Solution, Oral, as hydrobromide:

Razadyne: 4 mg/mL (100 mL [DSC]) [contains methylparaben, propylparaben, saccharin sodium]

Generic: 4 mg/mL (100 mL)

Tablet, Oral, as hydrobromide [strength expressed as base]:

Razadyne: 4 mg, 8 mg

Razadyne: 12 mg [contains fd&c yellow #6 aluminum lake]

Generic: 4 mg, 8 mg, 12 mg

Brand Names: U.S.

  • Razadyne
  • Razadyne ER

Pharmacologic Category

  • Acetylcholinesterase Inhibitor (Central)

Pharmacology

Centrally-acting cholinesterase inhibitor (competitive and reversible). It elevates acetylcholine in cerebral cortex by slowing the degradation of acetylcholine. Modulates nicotinic acetylcholine receptor to increase acetylcholine from surviving presynaptic nerve terminals. May increase glutamate and serotonin levels.

Distribution

175 L

Metabolism

Hepatic metabolism primarily via CYP2D6 to O-desmethyl-galantamine and 3A4 to galantamine-N-oxide; the activity of galantamine metabolites is not considered to be clinically relevant (Farlow 2003; Scott 2000)

Excretion

Urine (20%)

Time to Peak

Immediate release: 1 hour (2.5 hours with food); extended release: 4.5-5 hours

Half-Life Elimination

~7 hours

Protein Binding

18%

Special Populations: Renal Function Impairment

AUC increased 37% and 67% in moderate and severe renal function impairment.

Special Populations: Hepatic Function Impairment

Cl decreased about 25% in moderate (Child-Pugh score 7 to 9) hepatic function impairment.

Special Populations: Elderly

Concentrations are about 30% to 40% higher.

Special Populations: Gender

Cl is about 20% lower in women than in men.

Special Populations Note

CYP2D6 poor metabolizers: There is an approximate 35% increase in AUC of unchanged drug and 25% decrease in median Cl.

Use: Labeled Indications

Treatment of mild-to-moderate dementia of Alzheimer's disease

Use: Unlabeled

Severe dementia associated with Alzheimer's disease; mild-to-moderate dementia associated with Parkinson's disease; Lewy body dementia

Contraindications

Hypersensitivity to galantamine or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to other tertiary alkaloids

Dosing: Adult

Alzheimer dementia, mild-to-moderate: Oral:

Immediate-release tablet or solution: Initial: 4 mg twice daily for 4 weeks; if tolerated, increase to 8 mg twice daily for ≥4 weeks; if tolerated, increase to 12 mg twice daily. Range: 16 to 24 mg daily in 2 divided doses

Extended-release capsule: Initial: 8 mg once daily for 4 weeks; if tolerated, increase to 16 mg once daily for ≥4 weeks; if tolerated, increase to 24 mg once daily. Range: 16 to 24 mg once daily

Note: If therapy is interrupted for ≥3 days, restart at the lowest dose and increase to current dose.

Alzheimer dementia, severe (off-label use): Immediate-release tablet: Initial: 4 mg twice daily for 4 weeks; if tolerated, increase to 8 mg twice daily for ≥4 weeks; if tolerated, increase to 12 mg twice daily. May decrease to 8 mg twice daily if the target dose is not tolerated. Range: 16 to 24 mg daily in 2 divided doses (Burns 2009)

Dementia associated with Parkinson disease and Lewy body dementia (off-label use): Oral: American Psychiatric Association recommends dosing and titration similar to those for patients with Alzheimer disease (APA [Rabins 2007]).

Conversion from immediate release to extended release formulation: Patients may be switched from the immediate-release formulation to the extended-release formulation by taking the last immediate-release dose in the evening and beginning the extended-release dose the following morning; the same total daily dose should be used.

Conversion to galantamine from other cholinesterase inhibitors: Patients experiencing poor tolerability with donepezil or rivastigmine should wait until side effects subside or allow a 7-day washout period prior to beginning galantamine. Patients not experiencing side effects with donepezil or rivastigmine may begin galantamine therapy the day immediately following discontinuation of previous therapy (Morris 2001).

Dosing: Geriatric

Refer to adult dosing; adjust dose with caution in patients with low body weight and/or serious comorbidities.

Dosing: Renal Impairment

Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Moderate impairment (CrCl 9 to 59 mL/minute): Maximum dose: 16 mg daily.

Severe impairment (CrCl <9 mL/minute): Use is not recommended

Dosing: Hepatic Impairment

US labeling:

Mild impairment (Child-Pugh score 5 to 6): There are no dosage adjustments provided in the manufacturer’s labeling; however, single-dose galantamine pharmacokinetics were similar to that observed in healthy subjects.

Moderate impairment (Child-Pugh score 7 to 9): Maximum dose: 16 mg daily

Severe impairment (Child-Pugh score 10 to 15): Use is not recommended

Canadian labeling:

Mild impairment: (Child-Pugh score 5 to 6): There are no dosage adjustments provided in the manufacturer’s labeling; however, single-dose galantamine pharmacokinetics were similar to that observed in healthy subjects.

Moderate impairment: (Child-Pugh score 7 to 9): Initial: 8 mg every other day for at least 1 week, then increase to 8 mg once daily for at least 4 weeks (maximum dose: 16 mg daily)

Severe impairment (Child-Pugh score 10 to 15): Use is not recommended

Administration

Oral: Administer solution or tablet with breakfast and dinner; administer extended release capsule with breakfast. If therapy is interrupted for ≥3 days, restart at the lowest dose and increase to current dose. If using oral solution, mix dose with 3 to 4 ounces of any nonalcoholic beverage; mix well and drink immediately.

Dietary Considerations

Administration with food is preferred, but not required; should be taken with breakfast and dinner (tablet or solution) or with breakfast (capsule).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze oral solution.

Drug Interactions

Anticholinergic Agents: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Monitor therapy

Antipsychotic Agents: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Benoxinate: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy

Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Monitor therapy

Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Galantamine. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Monitor therapy

Succinylcholine: Acetylcholinesterase Inhibitors may increase the serum concentration of Succinylcholine. Management: Consider alternatives to this combination due to a risk of prolonged neuromuscular blockade. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse Reactions

>10%: Gastrointestinal: Nausea (21%), vomiting (11%)

1% to 10%:

Cardiovascular: Bradycardia (1%), syncope (1%)

Central nervous system: Dizziness (8%), headache (7%), depression (4%), falling (4%), fatigue (4%), drowsiness (2%), lethargy (1%), malaise (1%)

Endocrine & metabolic: Weight loss (5%)

Gastrointestinal: Decreased appetite (7%), diarrhea (7%), abdominal pain (4%), abdominal distress (2%), dyspepsia (2%)

Neuromuscular & skeletal: Tremor (2%), muscle spasm (1%)

Miscellaneous: Laceration (1%)

Frequency not defined:

Gastrointestinal: Anorexia

<1% (Limited to important or life-threatening): Acute generalized exanthematous pustulosis, anemia, aphasia, apraxia, arthritis, ataxia, atrial arrhythmia (includes atrial fibrillation and supraventricular tachycardia), atrioventricular block, bundle branch block, cardiac failure, cataract, cerebrovascular accident, convulsions, cystitis, dehydration (includes rare, severe cases leading to renal insufficiency and renal failure), delirium, dependent edema, diverticulitis, erythema multiforme, esophageal perforation, exacerbation of depression, gastroenteritis, hematuria, hepatitis, hyperglycemia, hyperhidrosis, hyperkinesia, hypersensitivity reaction, hypersomnia, hypertension, hypertonia, hypokalemia, hypokinesia, hypotension, increased liver enzymes, increased nonprotein nitrogen, increased serum alkaline phosphatase, inversion T wave on ECG, ischemic heart disease, lower GI bleeding, myocardial infarction, nephrolithiasis, orthostatic hypotension, paranoia, peripheral edema, pneumonia, prolonged Q-T interval on ECG, purpura, rectal hemorrhage, seizure, severe bradycardia, sinus bradycardia, Stevens-Johnson syndrome, suicidal ideation, supraventricular extrasystole, thrombocytopenia, transient ischemic attacks, trauma, upper gastrointestinal hemorrhage, urinary incontinence, urinary retention, urinary tract infection, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Skin reactions: Skin reactions including Stevens-Johnson syndrome, acute generalized exanthematous pustulosis and erythema multiforme have been reported. Treatment discontinuation may be necessary if skin reaction occurs; if rash is suspected to be drug related, do not resume galantamine and consider alternative therapy.

• Vagotonic effects: Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block with or without a history of cardiac disease.

• Weight loss: Weight loss has been observed; monitor body weight.

Disease-related concerns:

• Cardiac conduction abnormalities: Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer's treatment guidelines consider bradycardia to be a relative contraindication for use of centrally-active cholinesterase inhibitors.

• Hepatic impairment: Use with caution in patients with mild to moderate liver impairment; not recommended in severe impairment. Dose adjustment recommended in moderate impairment.

• Peptic ulcer disease: Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); may increase gastric acid secretion. Monitor for symptoms of bleeding.

• Renal impairment: Use with caution in patients with moderate renal impairment; not recommended in severe impairment (CrCl <9 mL/minute).

• Respiratory disease: Use with caution in patients with COPD and/or asthma.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

• Urinary tract obstruction: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Limited safety data in patients ≥85 years of age. Use with caution particularly in elderly patients with low body weight and/or serious comorbidities; adjust dose with caution.

Monitoring Parameters

Mental status; body weight

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or lack of appetite. Have patient report immediately to prescriber severe dizziness, passing out, bradycardia, arrhythmia, black, tarry, or bloody stools, vomiting blood, urinary retention, seizures, severe nausea, severe vomiting, severe diarrhea, excessive weight loss, tremors, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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