Galantamine

Special Alerts

Galantamine (Reminyl®): Warnings Concerning Preliminary Safety Information From Investigational Studies with Galantamine in Patients with Mild Cognitive Impairment - January 21, 2005

Johnson & Johnson Pharmaceutical Research & Development, LLC (J&JPRD) has announced that preliminary safety information from two investigational studies conducted with galantamine (Reminyl®) in patients with mild cognitive impairment (MCI) revealed an increase in mortality as compared to placebo. The GAL-INT-11 and GAL-INT-18 studies evaluated the rate of progression from mild cognitive impairment to dementia; over 2000 patients from 16 countries were enrolled. Although rates of mortality in both the galantamine treatment group and placebo group were low, 15 patients died while receiving treatment as compared to 5 deaths which occurred in individuals receiving placebo. Cardiovascular and cerebrovascular causes were thought to be associated with these deaths. Whether other drugs in this class have similar action when used for mild cognitive impairment is not known. Galantamine is not currently approved by the Food and Drug Administration (FDA) as treatment for mild cognitive impairment.

J&JPRD is currently reviewing additional data from these studies, including information gained from individuals who had dropped out of the trials, and is discussing this information with regulatory authorities.

A complete copy of the press announcement is available at: http://www.jnj.com/news/jnj_news/20050121_150033.htm

Additional information is available at http://www.clinicalstudyresults.org/ http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_advisories public e.html

Pronunciation

(ga LAN ta meen)

U.S. Brand Names

Reminyl®

Synonyms

Galantamine Hydrobromide

Generic Available

Canadian Brand Names

Reminyl®

Use

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

Pregnancy Risk Factor

Pregnancy Implications

In animal studies, there was a slight increased in the incident of skeletal variations when given during organogenesis. Adequate, well-controlled studies in pregnant women do not exist. Should be used in pregnancy only if benefit outweighs potential risk to the fetus.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to galantamine or any component of the formulation; severe liver dysfunction (Child-Pugh score 10-15); severe renal dysfunction (Clcr<9 mL/minute)

Warnings/Precautions

May exaggerate neuromuscular blockade effects of depolarizing neuromuscular-blocking agents like succinylcholine. Vagotonic effects on the SA and AV nodes may lead to bradycardia or AV block. Use caution in patients with supraventricular cardiac conduction delays (without a functional pacemaker in place) or patients taking concurrent medications that slow conduction through the SA or AV node. Use caution in peptic ulcer disease (or in patients at risk of ulcer disease); seizure disorder; asthma; COPD; mild to moderate liver dysfunction; moderate renal dysfunction. May cause bladder outflow obstruction. Safety and efficacy in children have not been established.

Adverse Reactions

>10%: Gastrointestinal: Nausea (6% to 24%), vomiting (4% to 13%), diarrhea (6% to 12%)

1% to 10%:

Cardiovascular: Bradycardia (2% to 3%), syncope (0.4% to 2.2%: dose related), chest pain ( 1%)

Central nervous system: Dizziness (9%), headache (8%), depression (7%), fatigue (5%), insomnia (5%), somnolence (4%), tremor (3%)

Gastrointestinal: Anorexia (7% to 9%), weight loss (5% to 7%), abdominal pain (5%), dyspepsia (5%), flatulence ( 1%)

Genitourinary: Urinary tract infection (8%), hematuria (<1% to 3%), incontinence ( 1%)

Hematologic: Anemia (3%)

Respiratory: Rhinitis (4%)

<1%: Alkaline phosphatase increase, apathy, aphasia, apraxia, ataxia, atrial fibrillation, AV block, bundle branch block, convulsions, cystitis, delirium, dependent edema, diverticulitis, dysphagia, epistaxis, esophageal perforation, gastritis, gastroenteritis, heart failure, hiccups, hyperglycemia, hypertonia, hypokinesia, hypotension, involuntary muscle contractions, libido increase, melena, increased micturition frequency, muscle weakness, nocturia, palpitation, paranoid reaction, paresthesia, paroniria, postural hypotension, purpura, QT prolongation, rectal hemorrhage, renal calculi, saliva increased, supraventricular tachycardia, T-wave inversion, thrombocytopenia, urinary retention, ventricular tachycardia, vertigo, xerostomia

Postmarketing and/or case reports: Aggression, dehydration, gastrointestinal bleeding, hypokalemia, renal failure (due to dehydration)

Overdosage/Toxicology

Symptoms of overdose may include bradycardia, collapse, convulsions, defecation, gastrointestinal cramping, hypotension, lacrimation, muscle fasciculations, muscle weakness, QT prolongation, respiratory depression, salivation, severe nausea, sweating, torsade de pointes, urination, ventricular tachycardia, vomiting. Treatment is symptom-directed and supportive. Atropine may be used as an antidote; initial dose 0.5-1 mg I.V. and titrate to effect. An atypical response in blood pressure and heart rate has been reported. Effects of hemodialysis are unknown.

Drug Interactions

Substrate (minor) of CYP2D6, 3A4

Amiodarone: Concurrent use may lead to bradycardia

Anticholinergic agents (eg, atropine, benztropine, tolterodine): Galantamine may antagonize anticholinergic actions

Beta blockers without ISA activity: Concurrent use may lead to bradycardia

Cimetidine: Increased bioavailability of galantamine by 16%

Cholinergic agonists: May have synergistic effects

Digoxin: Concurrent use may lead to AV block

Diltiazem: Concurrent use may lead to bradycardia

Ketoconazole: Increased galantamine levels (AUC increased by 30%)

NSAIDs: Concurrent use may increase risk of gastrointestinal ulcer because of increased gastric acid secretion.

Paroxetine: Increased galantamine levels (AUC increased by 40%)

Succinylcholine: Concurrent use may lead to enhanced neuromuscular blockade

Verapamil: Concurrent use may lead to bradycardia

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS adverse events).

Herb/Nutraceutical: St John's wort may decrease galantamine serum levels; avoid concurrent use.

Stability

Store at 15°C to 30°C (59°F to 86°F). Do not freeze oral solution; protect from light.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Duration: 3 hours; maximum inhibition of erythrocyte acetylcholinesterase ~40% at 1 hour post 10 mg oral dose; levels return to baseline at 30 hours

Absorption: Rapid and complete

Distribution: 1.8-2.6 L/kg; levels in the brain are 2-3 times higher than in plasma

Protein binding: 18%

Metabolism: Hepatic; linear, CYP2D6 and 3A4; metabolized to epigalanthaminone and galanthaminone both of which have acetylcholinesterase inhibitory activity 130 times less than galantamine

Bioavailability: 80% to 100%

Half-life elimination: 6-8 hours

Time to peak: 1 hour

Excretion: Urine (25%)

Dosage

Note: Take with breakfast and dinner. If therapy is interrupted for

3 days, restart at the lowest dose and increase to current dose.

Oral: Adults: Mild to moderate dementia of Alzheimer's: Initial: 4 mg twice a day for 4 weeks

If 8 mg per day tolerated, increase to 8 mg twice daily for 4 weeks

If 16 mg per day tolerated, increase to 12 mg twice daily

Range: 16-24 mg/day in 2 divided doses

Elderly: No dosage adjustment needed

Dosage adjustment in renal impairment:

Moderate renal impairment: Maximum dose: 16 mg/day.

Severe renal dysfunction (Clcr<9 mL/minute): Use is not recommended

Dosage adjustment in hepatic impairment:

Moderate liver dysfunction (Child-Pugh score 7-9): Maximum dose: 16 mg/day

Severe liver dysfunction (Child-Pugh score 10-15): Use is not recommended

Administration

Take with breakfast and dinner. If therapy is interrupted for

3 days, restart at the lowest dose and increase to current dose. If using oral solution, mix dose with 3-4 ounces of any nonalcoholic beverage; mix well and drink immediately.

Monitoring Parameters

Mental status

Dietary Considerations

Take with breakfast and dinner.

Patient Education

This medication will not cure Alzheimer's disease, but may help reduce symptoms. Use exactly as directed; do not increase dose or discontinue without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause dizziness, sedation, hypotension, or tremor (use caution when driving or engaging in hazardous tasks, rise slowly from sitting or lying position, and use caution when climbing stairs until response to drug is known); diarrhea (boiled milk, yogurt, or buttermilk may help); or nausea or vomiting (small, frequent meals, good mouth care, sucking lozenges, or chewing gum may help). Report persistent GI disturbances; significantly increased salivation, sweating, or tearing; excessive fatigue, insomnia, dizziness, or depression; increased muscle, joint, or body pain or spasms; vision changes; respiratory changes, wheezing, or signs of dyspnea; chest pain or palpitations; or other adverse reactions. Breast-feeding precaution: Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Solution, oral, as hydrobromide: 4 mg/mL (100 mL) [with calibrated pipette]

Tablet, as hydrobromide: 4 mg, 8 mg, 12 mg

References

Raskind MA, Peskind ER, Wessel T, et al, "Galantamine in AD: A 6-month Randomized, Placebo-controlled Trial With a 6-month Extension. The Galantamine USA-1 Study Group, Neurology , 2000, 54:2261-8.

Tariot PN, Solomon PR, Morris JC, et al, "A 5-month, Randomized, Placebo-controlled Trial of Galantamine in AD. The Galantamine USA-10 Study Group, Neurology , 2000, 54:2269-76.

International Brand Names

Nivalin® (HU, PL); Reminyl® (AT, BE, CA, CH, CZ, DE, DK, ES, FI, FR, GB, IE, IT, NO, NZ, PL, SE, SG, SI, TH, ZA)

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