Razadyne

Pronunciation

Generic Name: Galantamine Hydrobromide
Class: Parasympathomimetic (Cholinergic) Agents
VA Class: CN900
Chemical Name: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide
Molecular Formula: C17H21N03.HBr
CAS Number: 1953-04-4

Introduction

A centrally active, reversible acetylcholinesterase inhibitor.1

Uses for Razadyne

Alzheimer’s Disease

Palliative treatment of mild to moderate dementia of the Alzheimer’s type (Alzheimer’s disease); does not alter the underlying disease process of dementia.1

Slideshow: Flashback: FDA Drug Approvals 2013

Mild Cognitive Impairment

Has been investigated in patients with mild cognitive impairment who did not meet diagnostic criteria for Alzheimer’s disease but was associated with a higher incidence of death than placebo in these studies.1 (See Mortality under Cautions.) Not approved by FDA for this use, and manufacturer is not seeking approval.12

Razadyne Dosage and Administration

Administration

Oral Administration

Administer conventional tablets or oral solution orally twice daily, preferably with morning and evening meals.1

Administer extended-release capsules orally once daily in the morning, preferably with food.1

Administering the drug with food and using a slow escalation of dosage (i.e., increasing dosage at intervals ≥4 weeks) may reduce the incidence of adverse GI effects (e.g., nausea, vomiting).1 5

Administer oral solution using the graduated pipette provided by the manufacturer; refer to accompanying patient information for instructions.9 Dilute appropriate dose of oral solution in 100 mL of a nonalcoholic beverage just prior to administration and stir well; entire mixture should be consumed.9

Dosage

Available as galantamine hydrobromide; dosage is expressed in terms of galantamine.1

If galantamine therapy has been interrupted for more than a few days for any reason and reinitiation of the drug is not contraindicated, resume therapy using the lowest dosage and titrate upward to prior dosages.1

Adults

Alzheimer’s Disease
Oral

Initially, 4 mg twice daily (as conventional tablets or oral solution) or 8 mg once daily (as extended-release capsules).1 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

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

Maintenance dosage recommended by the manufacturer is 8–12 mg twice daily (as conventional tablets and oral solution) or 16–24 mg once daily (as extended-release capsules).1 Galantamine 16–24 mg once daily (as extended-release capsules) was as effective as galantamine 8–12 mg twice daily (as conventional tablets).1 Higher dosages (e.g., 16 mg twice daily) do not result in greater efficacy and are less well tolerated than lower dosages.1

Special Populations

Hepatic Impairment

Alzheimer’s Disease
Oral

Dosage generally should not exceed 16 mg daily in patients with moderate hepatic impairment (Child-Pugh score of 7–9).1 Use not recommended in patients with severe hepatic impairment (Child-Pugh score of 10–15).1

Renal Impairment

Alzheimer’s Disease
Oral

Dosage generally should not exceed 16 mg daily in patients with moderate renal impairment.1 Use not recommended in patients with severe renal impairment (Clcr <9 mL/minute).1

Cautions for Razadyne

Contraindications

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

Warnings/Precautions

Warnings

Cardiovascular Effects

Potential bradycardia, AV block, or other vagotonic effects on the heart.1

Patients with supraventricular cardiac conduction abnormalities and those receiving concomitant therapy with drugs that substantially decrease heart rate appear to be at particular risk, but may occur in any patient.1

Peptic Ulcers/GI Bleeding

Cholinesterase inhibitors may increase gastric acid secretion.1 Monitor closely for manifestations of active or occult GI bleeding, especially in patients at increased risk (e.g., history of ulcer disease, concomitant NSAIA therapy).1

GU Effects

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

Nervous System Effects

Potential for increased risk of seizures secondary to cholinergic activity (seizures also may be a manifestation of Alzheimer’s disease).1

Respiratory Effects

Use with caution in patients with a history of severe asthma or obstructive pulmonary disease because of increased cholinergic activity.1

Mortality

Higher incidence of death reported in patients receiving galantamine than in those receiving placebo in 2 studies in patients with mild cognitive impairment who did not meet diagnostic criteria for Alzheimer’s disease.1 Deaths were due to various causes expected in a geriatric population; approximately half in galantamine-treated patients were due to vascular causes (i.e., MI, stroke, sudden death).1 In addition, the incidence of mortality in placebo-treated patients in these 2 studies was substantially lower than that reported in placebo-treated patients in studies that evaluated galantamine in patients with Alzheimer’s disease.1

General Precautions

Prescribing and Dispensing Precautions

Similarity in spelling of Reminyl (the former trade name of galantamine) and Amaryl (glimepiride) has resulted in errors.10 11 In April 2005, manufacturer of galantamine announced that trade name would be changed from Reminyl to Razadyne to avoid future dispensing errors.13

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether galantamine is distributed into milk; use in nursing women is not currently indicated.1

Pediatric Use

Use not recommended.1

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment (Child-Pugh score of 10–15).1 Caution in patients with moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use not recommended in patients with severe renal impairment (Clcr <9 mL/minute).1 Caution in patients with moderate renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Conventional tablets: Nausea, vomiting, diarrhea, anorexia, weight decrease.1

Extended-release capsules: Adverse effect profile similar to that of conventional tablets.1

Interactions for Razadyne

Galantamine is metabolized by CYP, principally CYP2D6 and 3A4.1 Potential pharmacokinetic interactions (altered galantamine metabolism) with inhibitors or inducers of CYP2D6 and 3A4.1

Galantamine did not inhibit CYP1A2, CYP2A6, CYP3A4, CYP2C, CYP2D6, or CYP2E1 in vitro.1

Specific Drugs

Drug

Interaction

Amitriptyline

Decreased galantamine clearance1

Anesthesia

Exaggerated response to succinylcholine-type skeletal muscle relaxants during surgery1

Anticholinergics

Antagonistic effects1

Cholinomimetics and other cholinesterase inhibitors

Additive pharmacologic effects1 2

Cimetidine

Increased galantamine bioavailability1

Digoxin

Pharmacokinetic interaction unlikely1

Erythromycin

Increased galantamine AUC1

Fluoxetine

Decreased galantamine clearance1

Fluvoxamine

Decreased galantamine clearance1

Ketoconazole

Increased galantamine AUC1

Paroxetine

Increased galantamine bioavailability1

Quinidine

Decreased galantamine clearance1

Ranitidine

Pharmacokinetic interaction unlikely1

Warfarin

Pharmacokinetic interaction or effects on PT unlikely1

Razadyne Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability about 90%.1 Bioavailabilities of oral solution and tablets are equivalent.1 Extended-release capsules (24 mg once daily) and conventional tablets (12 mg twice daily) are bioequivalent when administered under fasting conditions.1

Peak plasma concentrations attained within 1 or 4.5–5 hours after administration of conventional tablets or extended-release capsules, respectively.1

Food

Conventional tablets or oral solution: Food did not affect the AUC, but peak plasma concentrations were decreased by 25% and time to peak plasma concentrations was delayed by 1.5 hours.1

Extended-release capsules: No appreciable differences in pharmacokinetic parameters following administration with food.1

Onset

Maximum inhibition of acetylcholinesterase (about 40%) achieved about 1 hour after a single 8-mg oral dose.1

Special Populations

Approximately 50% higher systemic exposure following administration of extended-release capsules in patients with reduced levels of CYP2D6 (also known as poor metabolizers); however, dosage adjustment is not necessary.1

Distribution

Extent

In whole blood, galantamine is mainly distributed to blood cells (52.7%).1 Blood to plasma concentration ratio is 1.2.1

Plasma Protein Binding

18% at therapeutically relevant concentrations.1

Elimination

Metabolism

Metabolized in the liver by CYP isoenzymes (principally CYP2D6 and 3A4).1

Clearance decreased 25% in patients with reduced levels of CYP2D6 activity; however, dosage adjustment is not necessary.1

Elimination Route

Principally in urine.1

Half-life

Terminal elimination half-life of about 7 hours.1

Special Populations

In patients with moderate hepatic impairment (Child-Pugh score of 7–9), clearance decreased by about 25% compared with healthy individuals.1 Exposure to the drug would be expected to increase further with increasing degree of hepatic impairment.1

In patients with moderate or severe renal impairment, AUC following a single 8-mg dose of galantamine (as conventional tablets) increased by 37% or 67%, respectively, compared with values in healthy individuals.1

Stability

Storage

Oral

Conventional Tablets and Extended-release Capsules

25°C; may be exposed to 15–30°C.1

Solution

25°C; may be exposed to 15–30°C.1 Do not freeze.1

Actions

  • Binds reversibly with and inactivates acetylcholinesterase, thus inhibiting hydrolysis of acetylcholine and increasing the concentration of acetylcholine at cholinergic synapses.1 2 7 Also binds allosterically with nicotinic acetylcholine receptors and may potentiate the action of agonists (e.g., acetylcholine) at these receptors.2 6 7

  • Effects may diminish as the Alzheimer’s disease process advances and fewer cholinergic neurons remain functioning.1

  • 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

Advice to Patients

  • Risk of adverse effects (e.g., nausea, vomiting, anorexia, weight loss).1

  • Importance of administering galantamine with food and ensuring adequate fluid intake.1

  • Importance of beginning therapy at 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 that questions about administration should be directed to their pharmacist or clinician.1 9

  • 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. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Galantamine Hydrobromide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

8 mg (of galantamine)

Razadyne ER

Ortho-McNeil

16 mg (of galantamine)

Razadyne ER

Ortho-McNeil

24 mg (of galantamine)

Razadyne ER

Ortho-McNeil

Solution

4 mg/mL (of galantamine)

Razadyne (with parabens)

Ortho-McNeil

Tablets, film-coated

4 mg (of galantamine)

Razadyne (with propylene glycol)

Ortho-McNeil

8 mg (of galantamine)

Razadyne (with propylene glycol)

Ortho-McNeil

12 mg (of galantamine)

Razadyne (with propylene glycol)

Ortho-McNeil

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Galantamine Hydrobromide 16MG 24-hr Capsules (TEVA PHARMACEUTICALS USA): 30/$119.99 or 90/$335.96

Galantamine Hydrobromide 8MG 24-hr Capsules (TEVA PHARMACEUTICALS USA): 30/$118.99 or 90/$335.96

Galantamine Hydrobromide 8MG Tablets (MYLAN): 30/$69.99 or 90/$195.97

Razadyne 12MG Tablets (JANSSEN): 30/$112.16 or 90/$314.05

Razadyne 4MG Tablets (JANSSEN): 30/$109.99 or 90/$329.96

Razadyne 8MG Tablets (JANSSEN): 30/$112.16 or 90/$314.05

Razadyne ER 16MG 24-hr Capsules (JANSSEN): 30/$225.98 or 90/$629.96

Razadyne ER 24MG 24-hr Capsules (JANSSEN): 30/$225.98 or 90/$625.99

Razadyne ER 8MG 24-hr Capsules (JANSSEN): 30/$225.98 or 90/$629.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Ortho-McNeil Neurologics, Inc. Razadyne ER (galantamine HBr extended-release capsules) and Razadyne (galantamine HBr tablets and oral solution) prescribing information. Titusville, NJ; 2005 Jun.

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. [IDIS 449306] [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. [IDIS 449305] [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. [IDIS 441746] [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.

9. Janssen Pharmaceutica Products, L.P. Patient information: using your Reminyl dispensing-pipette and bottle. Titusville, NJ; 2001 Jun.

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. Hulihan, J. Dear healthcare professional letter: Important safety alert regarding deaths in subjects with mild cognitive impairment (MCI). Titusville, NJ: Ortho-McNeil Neurologics; 2005 Mar 31.

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

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