VA Class:CN900

AHFS Class:

• Parasympathomimetic (Cholinergic) Agents 12:04

Generic Name(s):

• Galantamine Hydrobromide

Chemical Name:

• (4a S ,6 R ,8a S )-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6 H -benzofuro[3a,3,2- ef ][2]benzazepin-6-ol hydrobromide

Molecular Formula:

• C₁₇H₂₁N0₃•HBr

Galantamine hydrobromide is a centrally active, reversible acetylcholinesterase inhibitor.1

Alzheimer's Disease

Galantamine hydrobromide is used for the management of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease).1,  15,  20

Cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) are used for the symptomatic management of dementia associated with Alzheimer's disease; there is no evidence that these drugs alter the course of the underlying dementing process.1,  20,  21,  22,  23,  25,  26 The rationale for use of cholinesterase inhibitors in patients with Alzheimer's disease is to increase CNS acetylcholine concentrations, which are deficient in these patients (see Description).20,  21,  22 Since there is no cure for dementia,20,  23 the goal of treatment is to improve quality of life and maximize functional ability.23 The available evidence is modest for the efficacy of cholinesterase inhibitors in the treatment of mild to severe Alzheimer's disease.20,  21,  22,  23 Randomized controlled studies conducted with these drugs have shown only modest benefits in cognitive and functional measures, and the clinical importance of these effects is not clear.20,  21,  22,  23,  25,  26 Because of the lack of established alternatives, experts generally recommend a trial with one of the cholinesterase inhibitors in patients with mild to moderate Alzheimer's disease; there is also evidence suggesting that these drugs may have some limited benefits in patients with severe disease.20,  21,  22,  23 Although few comparative trials have been conducted, the available evidence suggests that efficacy is similar among the various cholinesterase inhibitors, but tolerability may differ.20,  21,  22 The long-term efficacy of cholinesterase inhibitors in patients with Alzheimer's disease is not clear, and additional studies are needed to determine whether the benefits of these drugs are sustained; however, there is evidence indicating that adverse effects such as anorexia, weight loss, syncope, bradycardia, falls, hip fractures, and increased need for cardiac pacemakers may develop with long-term use.21,  22,  25,  26

Efficacy of galantamine has been demonstrated in 5 randomized, placebo-controlled studies of 3-6 months' duration in patients diagnosed with probable Alzheimer's disease utilizing a dual outcome assessment strategy; 4 of these studies evaluated conventional tablets, and 1 study evaluated extended-release capsules.1 Changes in cognitive performance were assessed by various instruments, including the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), and changes in overall clinical effects were assessed using the Clinician's Interview Based Impression of Change that required the use of caregiver information (CIBIC plus).1,  2,  3,  4,  5 Overall, galantamine 8-16 mg twice daily (as conventional tablets) was found to be more effective than placebo for improvements in cognitive function and overall clinical status as assessed by the ADAS cog and CIBIC plus scales.1,  3,  4,  5 In a 6-month study, galantamine 16-24 mg once daily (as extended-release capsules) was as effective as galantamine 8-12 mg twice daily (as conventional tablets) and more effective than placebo in improving cognitive function and overall daily function as assessed by the ADAS cog and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scales, respectively; however, galantamine extended-release capsules were not more effective than placebo in improving overall clinical status (as assessed by the CIBIC plus scale).1 In a 6-month extension of a randomized, placebo-controlled study using galantamine conventional tablets, clinical improvements were maintained over a 12-month study period in patients who continued to receive galantamine therapy.5 However, as with other cholinesterase inhibitors,8 improvement associated with galantamine therapy was not maintained following discontinuance of the drug, suggesting that galantamine does not alter the underlying disease process of dementia.1

Mild Cognitive Impairment

Galantamine has been investigated in patients with mild cognitive impairment† who did not meet diagnostic criteria for Alzheimer's disease.1 However, the incidence of death in patients receiving galantamine was higher than the incidence in those receiving placebo in 2 randomized controlled studies in patients with mild cognitive impairment.1 (See Mortality under Cautions: Warnings/Precautions.) Galantamine is not approved by FDA for use in patients with mild cognitive impairment who do not have Alzheimer's disease.12

Results of a systematic review of 9 randomized, double-blind, placebo-controlled studies of cholinesterase inhibitors in patients with mild cognitive impairment showed no substantial evidence of a beneficial effect on progression to dementia and essentially no effect of these drugs on cognitive test scores.27 An increased risk of adverse effects, particularly GI effects, was observed with these drugs.27 These findings do not support the use of cholinesterase inhibitors in individuals presenting with memory complaints who do not meet diagnostic criteria for dementia.27

Administration

Galantamine hydrobromide conventional tablets and oral solution are administered orally twice daily, preferably with morning and evening meals.1,  15,  16 The extended-release capsules are administered orally once daily in the morning, preferably with food.1,  14

Slow dosage escalation is recommended to reduce the incidence of adverse cholinergic effects; a minimum of 4 weeks at the prior dosage is recommended before dosage is increased.1,  15

Patients should ensure adequate intake of fluids during treatment.1,  15

The oral solution should be administered using the dosing syringe provided by the manufacturer, referring to the accompanying patient information for instructions.15 The appropriate dose should be diluted in 100 mL of a nonalcoholic beverage just prior to administration; the mixture should be stirred well and consumed immediately.15

Dispensing and Administration Precautions

Because similarity in spelling between Reminyl^® (the former trade name for galantamine hydrobromide) and Amaryl^® (the trade name for glimepiride, a sulfonylurea antidiabetic agent) previously has resulted in dispensing errors,10,  11,  13 the manufacturer of Reminyl^® announced in April 2005 that the trade name for galantamine hydrobromide would be changed from Reminyl^® to Razadyne^® to avoid future dispensing errors.13 (See Dispensing and Administration Precautions under Cautions: Warnings/Precautions.)

Dosage

Dosage of galantamine hydrobromide is expressed in terms of galantamine.1,  14,  15,  16

The recommended initial adult dosage of galantamine for the management of mild to moderate Alzheimer's disease is 4 mg twice daily (as conventional tablets or oral solution) or 8 mg once daily (as extended-release capsules). 1,  15 Dosage may be increased after a minimum of 4 weeks to 8 mg twice daily (as conventional tablets or oral solution) or 16 mg once daily (as extended-release capsules).1,  15 Subsequent increases to 12 mg twice daily (as conventional tablets or oral solution) or 24 mg once daily (as extended-release capsules) should be attempted after a minimum of 4 weeks of treatment at the previous dosage.1,  15 Dosage increments should be based on clinical assessment of benefit and tolerance of the previous dosage.1,  15 The recommended maintenance dosage is 8-12 mg twice daily (as conventional tablets or oral solution) or 16-24 mg once daily (as extended-release capsules).1,  15 Higher dosages (e.g., 16 mg twice daily) do not result in greater efficacy and are less well tolerated than lower dosages.1,  15

If galantamine therapy has been interrupted for more than 3 days, therapy should be restarted using the lowest dosage and titrated upward to the prior dosage.1

Special Populations

In patients with moderate hepatic impairment (Child-Pugh score of 7-9), dosage of galantamine generally should not exceed 16 mg daily.1 Use of the drug is not recommended in patients with severe hepatic impairment (Child-Pugh score of 10-15).1

In patients with creatinine clearance of 9-59 mL/minute, dosage of galantamine generally should not exceed 16 mg daily.1 Use of the drug is not recommended in patients with creatinine clearance less than 9 mL/minute.1

Contraindications

Known hypersensitivity to galantamine hydrobromide or any ingredient in the formulation.1

Warnings/Precautions

Cardiovascular Effects

Cholinesterase inhibitors such as galantamine may produce bradycardia, atrioventricular (AV) block, or other vagotonic effects on the heart.1 Although patients with supraventricular cardiac conduction abnormalities and those receiving concomitant therapy with drugs that substantially decrease heart rate appear to be at particular risk, these adverse cardiovascular effects may occur in any patient.1 Cholinesterase inhibitors should be used with caution in patients with sick sinus syndrome or other conduction defects.20

GI Effects

Adverse GI effects associated with cholinesterase inhibitors include diarrhea, nausea, vomiting, and weight loss.1,  20 These effects are dose related and are usually mild to moderate in severity.1,  20 The manufacturer recommends that patient weight should be monitored during galantamine therapy.1

Peptic Ulcers/GI Bleeding

Cholinesterase inhibitors such as galantamine may increase gastric acid secretion.1 Patients should be monitored closely for manifestations of active or occult GI bleeding, especially in patients with increased risk (e.g., history of ulcer disease, concomitant nonsteroidal anti-inflammatory agent [NSAIA] therapy).1

In clinical studies, the incidence of peptic ulcer disease or GI bleeding was not increased with galantamine compared with placebo.1

Genitourinary Effects

Although not reported in clinical studies with galantamine, cholinomimetic agents may cause bladder outflow obstruction.1

Neurologic Effects

Drugs that increase cholinergic activity have the potential for causing seizures; however, seizures also may be a manifestation of Alzheimer's disease.1 These drugs should be used with caution in patients with seizures.20

Respiratory Effects

Like other drugs that increase cholinergic activity, galantamine should be used with caution in patients with a history of severe asthma or obstructive pulmonary disease.1

Mortality

In 2 controlled studies of 2 years' duration in patients with mild cognitive impairment who did not meet diagnostic criteria for Alzheimer's disease, the incidence of death in those randomized to receive galantamine was higher than in those randomized to receive placebo (10.2 per 1000 person-years compared with 0.7 per 1000 person-years, respectively).1 The deaths were attributed to various causes that would be expected in a geriatric population; approximately half of the deaths in patients receiving galantamine were attributed to vascular causes (i.e., myocardial infarction, stroke, sudden death).1 Although the difference in mortality was significant, it should be noted that the incidence of mortality in these 2 studies differs from the incidence observed in other placebo-controlled studies that evaluated galantamine.1 The incidence of death in placebo-treated patients with mild cognitive impairment was substantially lower than the incidence observed in clinical studies in placebo-treated patients with Alzheimer's disease (0.7 per 1000 person-years compared with 21-61 per 1000 person-years, respectively).1 In addition, the incidence of death in galantamine-treated patients with mild cognitive impairment was lower than the incidence observed in clinical studies in galantamine-treated patients with Alzheimer's disease (10.2 per 1000 person-years compared with 23-31 per 1000 person-years, respectively).1 In the studies in patients with mild cognitive impairment, no placebo-treated patient died after 6 months, an unexpected finding in this age group.1

Sensitivity Reaction

Serious Skin Reactions

Serious skin reactions such as Stevens-Johnson syndrome and acute generalized exanthematous pustulosis have been reported in patients receiving galantamine.1 The drug should be discontinued at the first sign of a skin rash unless the rash is clearly not drug related.1 If the rash is severe, galantamine therapy should not be resumed and alternative treatment should be considered.1

Dispensing and Administration Precautions

Because of similarity in spelling between Reminyl^® (the former trade name for galantamine) and Amaryl^® (the trade name for glimepiride, a sulfonylurea antidiabetic agent), dispensing errors resulting in serious adverse events (e.g., severe hypoglycemia, death) have been reported.10,  11,  13 Therefore, in April 2005, the manufacturer of Reminyl^® announced that the trade name for galantamine hydrobromide would be changed from Reminyl^® to Razadyne^® to avoid future dispensing errors.13

Specific Populations

Pregnancy

There are no adequate data to inform the developmental risks associated with the use of galantamine in pregnant women.1 Animal reproduction studies revealed some evidence of developmental toxicity when the drug was administered to pregnant rats and rabbits during the period of organogenesis at doses similar to or higher than those used clinically.1

Lactation

It is not known whether galantamine is distributed into milk of if the drug has any effects on the nursing infant or milk production.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for galantamine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of galantamine have not been established in pediatric patients.1

Hepatic Impairment

Use of galantamine is not recommended in patients with severe hepatic impairment (Child-Pugh score of 10-15).1 Dosage modification is recommended in patients with moderate hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Use of galantamine is not recommended in patients with severe renal impairment (creatinine clearance less than 9 mL/minute).1 Dosage modification is recommended in patients with moderate renal impairment.1 (See Dosage and Administration: Special Populations.)

Geriatric Use

The mean age of patients receiving galantamine in clinical studies was 75 years; 78% of patients were 65-84 years of age and 10% were 85 years of age or older.1

Common Adverse Effects

Adverse effects reported in 5% or more of patients receiving galantamine hydrobromide include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite.1 Most adverse effects associated with galantamine occurred during upward titration of dosages.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Galantamine is metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP2D6 and CYP3A4.1 Pharmacokinetic interactions are possible when galantamine is used concomitantly with drugs that inhibit or induce these isoenzymes.1

In vitro studies indicate that galantamine does not inhibit CYP isoenzyme 1A2, 2A6, 3A4, 2C, 2D6, or 2E1.1

CYP3A4 Inhibitors

Ketoconazole, a potent inhibitor of CYP3A4 and also an inhibitor of CYP2D6, increases systemic exposure of galantamine by 30%.1 However, erythromycin, a moderate inhibitor of CYP3A4, increased systemic exposure of galantamine by only 10%.1

CYP2D6 Inhibitors

Population pharmacokinetic analysis showed that clearance of galantamine was reduced by about 25-33% following concomitant administration of several drugs that are known to inhibit CYP2D6 (e.g., amitriptyline, fluoxetine, fluvoxamine, quinidine).1

Paroxetine, a potent inhibitor of CYP2D6, increased oral bioavailability of galantamine by about 40%.1

Anticholinergic Agents

Galantamine may interfere with the activity of anticholinergic agents.1

Cholinomimetics and other Cholinesterase Inhibitors

A synergistic effect is expected when galantamine is administered concomitantly with cholinergic agonists and other cholinesterase inhibitors.1

Digoxin

Galantamine had no effect on the steady-state pharmacokinetics of digoxin; however, a healthy individual who received the drugs in combination developed second- and third-degree heart block and bradycardia requiring hospitalization.1

Histamine H2-Receptor Antagonists

Cimetidine increased the bioavailability of galantamine by approximately 16% while ranitidine had no effect on the pharmacokinetics of galantamine.1

Memantine

Memantine had no effects on the steady-state pharmacokinetics of galantamine.1

Neuromuscular Blocking Agents

A synergistic effect is expected when galantamine is administered concomitantly with neuromuscular blocking agents such as succinylcholine.1

Warfarin

Galantamine had no effects on the pharmacokinetics of R - or S -warfarin or on prothrombin time (PT).1 Galantamine also did not affect protein binding of warfarin.1

Description

Galantamine hydrobromide, a phenanthrene alkaloid, is a reversible, competitive acetylcholinesterase inhibitor that is structurally unrelated to other acetylcholinesterase inhibitors (e.g, donepezil, rivastigmine, tacrine).1,  2,  6,  7

The precise mechanism(s) of action of galantamine in patients with dementia of the Alzheimer's type (Alzheimer's disease) has not been fully elucidated.1 Galantamine is an anticholinesterase agent that binds reversibly with and inactivates acetylcholinesterase, thus inhibiting hydrolysis of acetylcholine and increasing the concentration of acetylcholine at cholinergic synapses.1,  2,  7 The drug also binds allosterically with nicotinic acetylcholine receptors and may potentiate the action of agonists (e.g., acetylcholine) at these receptors.2,  6,  7 Because a deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits,2,  7,  22,  28 enhancement of cholinergic function with an anticholinesterase agent, such as galantamine, is one of the pharmacologic approaches to treatment.1,  2,  7,  22,  28 The deficiency of cholinergic transmission in Alzheimer's disease has been associated with the accumulation of β-amyloid peptide and neurofibrillary tangles that is characteristic of the disease.22,  28 Galantamine's effect may diminish as the disease process advances and fewer cholinergic neurons remain functioning.1

Galantamine is metabolized by hepatic cytochrome P-450 (principally CYP2D6 and 3A4) isoenzymes and by glucuronidation; the drug also is excreted unchanged in the urine.1

Advice to Patients

Risk of adverse effects such as nausea, vomiting, anorexia, and weight loss.1 Importance of administering galantamine with food and ensuring adequate fluid intake.1

Importance of beginning therapy at the lowest dosage and gradually increasing back to prior dosage range if therapy is interrupted for any reason.1

Importance of understanding the proper procedure for administering the oral solution, including review of the patient information provided by the manufacturer; advise patients to direct questions about administration to their pharmacist or clinician.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

1. Janssen Pharmaceuticals. Razadyne^® ER (galantamine extended-release capsules) and Razadyne^® (galantamine tablets) prescribing information. Titusville, NJ; 2020 Mar.

2. Scott LJ, Goa KL. Galantamine: a review of its use in Alzheimer's disease. Drugs . 2000; 60:1095-122. [PubMed 11129124]

3. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. Br Med J . 2000; 321:1445-9.

4. Tariot PN, Solomon PR, Morris JC et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology . 2000; 54:2269-76. [PubMed 10881251]

5. Raskind MA, Peskind ER, Wessel T et al. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology . 2000; 54:2261-8. [PubMed 10881250]

6. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. Drug Saf . 1998; 19:465-80. [PubMed 9880090]

7. Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry . 2000; 157:4-15. [PubMed 10618007]

8. American Psychiatric Association. Practice guidelines for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatry . 1997; 154(Suppl 5):1-39.

10. Mahmoud R. Dear healthcare professional letter: Important safety alert regarding medication errors. Titusville, NJ: Janssen Pharmaceutica, Inc; 2004 Oct 15.

11. Mahmoud R. Dear pharmacist letter: Important safety alert regarding medication errors. Titusville, NJ: Janssen Pharmaceutica, Inc; 2004 Oct 19.

12. Huliham J. Dear healthcare professional letter: Important prescribing information. Titus, NJ: Ortho-McNeill Neurologics; 2005 Mar 15.

13. Ortho-McNeil Neurologics. Reminyl^® renamed Razadyne^® in U.S. to support patient safety. Titusville, NJ; 2005 Apr 11. Press release.

14. Actavis. Galantamine extended-release capsules prescribing information. Parsippany, NJ; 2020 Mar.

15. West-ward Pharmaceuticals. Galantamine oral solution prescribing information. Eatontown, NJ; 2020 Mar.

16. American Health Packaging. Galantamine tablets prescribing information. Columbus, OH; 2017 Mar.

20. APA Work Group on Alzheimer's Disease and other Dementias, Rabins PV, Blacker D, Rovner BW et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition. Am J Psychiatry. 2007;164(12 Suppl):5-56. Copy Download .nbib Format: AMA MLA APA NLM [PubMed 18340692]

21. Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ). 2017;15(1):110-128. doi:10.1176/appi.focus.15106 [PubMed 31997970]

22. Winslow BT, Onysko MK, Stob CM, Hazlewood KA. Treatment of Alzheimer disease [published correction appears in Am Fam Physician. 2014 Aug 15;90(4):209]. Am Fam Physician. 2011;83(12):1403-1412. [PubMed 21671540]

23. American Geriatrics Society. A guide to dementia diagnosis and treatment. [Web]

24. Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther. 2010;32(7):1234-1251. doi:10.1016/j.clinthera.2010.06.019 [PubMed 20678673]

25. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2018;6(6):CD001190. Published 2018 Jun 18. doi:10.1002/14651858.CD001190.pub3 [PubMed 29923184]

26. Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer's disease [published online ahead of print, 2015 Sep 22]. Cochrane Database Syst Rev. 2015;9(9):CD001191. doi:10.1002/14651858.CD001191.pub4

27. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012;2012(9):CD009132. Published 2012 Sep 12. doi:10.1002/14651858.CD009132.pub2 [PubMed 22972133]

28. Querfurth HW, LaFerla F. Alzheimer's disease. NEJM. 2010; 362: 329-44. [Web]