Drugs Details

Drugs Info of Razadyne, Razadyne ER
Drugs Details
  • Drugs Type  : FDA
  • Date : 18th Mar 2015 04:35 am
  • Brand Name : Razadyne, Razadyne ER
  • Generic Name : galantamine (Pronunciation: ga LAN ta meen)
Descriptions

RAZADYNE® ER capsules, RAZADYNE® tablets, and RAZADYNE® oral solution contain galantamine, a reversible, competitive acetylcholinesterase inhibitor, as the hydrobromide salt. Galantamine hydrobromide is known chemically as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3­methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide. It has an empirical formula of C17H21NO3 •HBr and a molecular weight of 368.27. Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water. The structural formula for galantamine hydrobromide is:

 

RAZADYNE®  ER (galantamine hydrobromide) Structural Formula Illustration

RAZADYNE® ER extended-release capsules contain 8 mg, 16 mg, and 24 mg galantamine as 10.25 mg, 20.51 mg, and 30.76 mg of galantamine hydrobromide, respectively. Inactive ingredients include diethyl phthalate, ethylcellulose, gelatin, hypromellose, polyethylene glycol, sugar spheres (sucrose and starch), and titanium dioxide. The 16 mg capsule also contains red ferric oxide. The 24 mg capsule also contains red ferric oxide and yellow ferric oxide.

RAZADYNE® tablets contain 4 mg, 8 mg, and 12 mg galantamine as 5.126 mg, 10.253 mg, and 15.379 mg of galantamine hydrobromide, respectively. Inactive ingredients include colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol, talc, and titanium dioxide. The 4 mg tablets contain yellow ferric oxide. The 8 mg tablets contain red ferric oxide. The 12 mg tablets contain red ferric oxide and FD&C yellow #6 aluminum lake.

RAZADYNE® oral solution contains 4 mg galantamine (as 5.13 mg galantamine hydrobromide) per mL. The inactive ingredients are methylparaben, propylparaben, purified water, sodium hydroxide, and saccharin sodium.

What are the possible side effects of galantamine (Razadyne, Razadyne ER)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using galantamine and call your doctor at once if you have a serious side effect such as:

  • chest pain, slow heart rate;
  • feeling like you might pass out;
  • blood in your urine or stool;
  • coughing up blood or vomit that looks like coffee grounds;
  • painful or difficult urination;
  • urinating less than usual or not at all;
  • weakness, confusion, decreased...

Read All Potential Side Effects and See Pictures of Razadyne ER »

What are the precautions when taking galantamine hbr er (Razadyne ER)?

Before taking galantamine, tell your doctor or pharmacist if you are allergic to it; or to daffodil plants; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe liver disease, severe kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, kidney problems, stomach/intestinal problems (e.g., ulcers, bleeding), heart problems (e.g., sick sinus syndrome, bradycardia, AV block, arrhythmias), breathing/lung problems (e.g.,...

Read All Potential Precautions of Razadyne ER »

This monograph has been modified to include the generic and brand name in many instances.

Indications

RAZADYNE® ER and RAZADYNE® are indicated for the treatment of mild to moderate dementia of the Alzheimer's type.

Dosage Administration

RAZADYNE® ER Extended-Release Capsules

RAZADYNE® ER extended-release capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of RAZADYNE® ER is 8 mg/day. The dosage should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks. A further increase to 24 mg/day should be attempted after a minimum of 4 weeks at 16 mg/day. Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

The dosage of RAZADYNE® ER shown to be effective in a controlled clinical trial is 16-24 mg/day.

Patients currently being treated with RAZADYNE® tablets or oral solution can convert to RAZADYNE® ER (extended-release capsules) by taking their last dose of RAZADYNE® tablets or oral solution in the evening and starting RAZADYNE® ER once daily treatment the next morning. Converting from RAZADYNE® to RAZADYNE® ER should occur at the same total daily dosage.

RAZADYNE® Immediate-Release Tablets And Oral Solution

The dosage of RAZADYNE® tablets shown to be effective in controlled clinical trials is 16-32 mg/day given as twice daily dosing. As the dosage of 32 mg/day is less well tolerated than lower dosages and does not provide increased effectiveness, the recommended dosage range is 16-24 mg/day given twice daily. The dosage of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dosage of 24 mg of RAZADYNE® might provide additional benefit for some patients.

The recommended starting dosage of RAZADYNE® tablets and oral solution is 4 mg twice a day (8 mg/day). The dosage should be increased to the initial maintenance dosage of 8 mg twice a day (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice a day (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice a day (16 mg/day).

Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

RAZADYNE® tablets and oral solution should be administered twice a day, preferably with morning and evening meals.

Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose.

The abrupt withdrawal of RAZADYNE® ER and RAZADYNE® in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. The beneficial effects of RAZADYNE® ER and RAZADYNE® are lost, however, when the drug is discontinued.

Dosage In Patients With Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh score of 7-9), the dosage should generally not exceed 16 mg/day. The use of RAZADYNE® ER and RAZADYNE® in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended [see CLINICAL PHARMACOLOGY].

Dosage In Patients With Renal Impairment

In patients with creatinine clearance of 9 to 59 mL/min, the dosage should generally not exceed 16 mg/day. In patients with creatinine clearance less than 9 mL/min, the use of RAZADYNE® ER and RAZADYNE® is not recommended [see CLINICAL PHARMACOLOGY].

How Supplied

Dosage Forms And Strengths

RAZADYNE® ER extended-release capsules contain white to off-white pellets and are available in the following strengths:

8 mg white opaque, size 4 hard gelatin capsule with the inscription “GAL 8”

16 mg pink opaque, size 2 hard gelatin capsule with the inscription “GAL 16”

24 mg caramel opaque, size 1 hard gelatin capsule with the inscription “GAL 24”

RAZADYNE® tablets are available in the following strengths:

4 mg circular biconvex, off-white tablet imprinted with “JANSSEN” on one side and “G 4” on the other side

8 mg circular biconvex, pink tablet imprinted with “JANSSEN” on one side and “G 8” on the other side

12 mg circular biconvex, orange-brown tablet imprinted with “JANSSEN” on one side and “G 12” on the other side

RAZADYNE® 4 mg/mL oral solution is a clear colorless solution supplied in 100 mL bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume is 0.5 mL, while the maximum calibrated volume is 4 mL.

RAZADYNE® ER (galantamine hydrobromide) extended-release capsules are supplied as follows:

8 mg white opaque, size 4 hard gelatin capsules with the inscription “GAL 8” – bottles of 30 NDC 50458-387-30

16 mg pink opaque, size 2 hard gelatin capsules with the inscription “GAL 16” – bottles of 30 NDC 50458-388-30

24 mg caramel opaque, size 1 hard gelatin capsules with the inscription “GAL 24” – bottles of 30 NDC 50458-389-30

RAZADYNE® (galantamine hydrobromide) tablets are supplied as follows:

4 mg circular biconvex, off-white tablets imprinted with “JANSSEN” on one side and “G 4” on the other side – bottles of 60 NDC 50458-396-60

8 mg circular biconvex, pink tablets imprinted with “JANSSEN” on one side and “G 8” on the other side – bottles of 60 NDC 50458-397-60

12 mg circular biconvex, orange-brown tablets imprinted with “JANSSEN” on one side and “G 12” on the other side – bottles of 60 NDC 50458-398-60

RAZADYNE® (galantamine hydrobromide) oral solution is supplied as follows:

4 mg/mL clear colorless oral solution – 100 mL bottle NDC 50458-490-10

Storage And Handling

RAZADYNE® ER extended-release capsules should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

RAZADYNE® tablets should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

RAZADYNE® oral solution should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE.

Keep out of reach of children.

Manufactured by: Janssen Pharmaceutica NV Olen, Belgium. Extended-release capsules and tablets are manufactured by: Janssen Ortho LLC Gurabo, Puerto Rico 00778. Oral solution is manufactured by: Janssen Pharmaceutica NV Beerse, Belgium. Extended-release capsules, tablets, and Oral solution are manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. Revised: Feb 2015

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

Serious adverse reactions are discussed in more detail in the following sections of the labeling:

  • Serious skin reactions [see WARNINGS AND PRECAUTIONS]
  • Deaths in subjects with mild cognitive impairment (MCI) [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions in galantamine-treated patients from double-blind clinical trials ( ≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, decreased appetite, and weight decreased.

The most common adverse reactions associated with discontinuation ( ≥ 1%) in galantamine-treated patients from double-blind clinical trials were nausea (7.7%), vomiting (4.1%), decreased appetite (1.9%), and dizziness (1.6%).

The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 2932 galantamine-treated patients who participated in 7 placebo-controlled clinical studies and 1454 subjects in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer's type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with tablets. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Table 1 lists the adverse reactions reported in ≥ 1% of galantamine-treated patients in 7 placebo-controlled, double-blind clinical trials.

Table 1: Adverse Reactions Reported by ≥ 1% of Galantamine-Treated Patients in Pooled Placebo-Controlled, Double-Blind Clinical Trials

System/Organ Class
Adverse Reaction
Galantamine
(n=2932) %
Placebo
(n=1525) %
Metabolism and Nutrition Disorders
  Decreased appetite 5.2 1.4
  Anorexia 3.8 1.0
Psychiatric Disorders
  Depression 4.2 2.9
Nervous System Disorders
  Dizziness 8.9 4.6
  Headache 7.6 5.4
  Tremor 2.0 0.8
  Syncope 1.8 0.7
  Lethargy 1.7 0.7
  Somnolence 1.7 0.8
Cardiac Disorders
  Bradycardia 1.2 0.3
Gastrointestinal Disorders
  Nausea 25.0 7.6
  Vomiting 12.8 3.1
  Diarrhea 9.0 6.3
  Abdominal pain 2.4 0.9
  Upper abdominal pain 2.0 1.4
  Dyspepsia 1.8 1.3
  Stomach discomfort 1.6 0.6
  Abdominal discomfort 1.0 0.4
Skin and Subcutaneous Tissue Disorders
  Hyperhidrosis 1.2 0.7
Musculoskeletal and Connective Tissue Disorders
  Muscle spasms 1.5 0.8
General Disorders and Administration Site Conditions
  Fatigue 4.0 2.2
  Asthenia 2.3 1.7
  Malaise 1.4 0.7
Investigations
  Decreased weight 5.1 1.4

The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5-7 days.

Other Adverse Reactions Observed in Clinical Trials of Galantamine

The following adverse reactions occurred in < 1% of all galantamine-treated patients (N=2932) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in patients (N=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below:

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Dysgeusia, Hypersomnia, Paresthesia

Eye Disorders: Blurred vision

Cardiac Disorders: First degree atrioventricular block, Palpitations, Sinus bradycardia, Supraventricular extrasystoles

Vascular Disorders: Flushing, Hypotension

Gastrointestinal Disorders: Retching

Musculoskeletal and Connective Tissue Disorders: Muscular weakness

Injury, Poisoning and Procedural Complications: Fall

Discontinuations Due to Adverse Reactions

In the 7 placebo-controlled studies of adults, 379 (12.9%) galantamine-treated patients (N=2932) and 42 (2.8%) placebo patients (N=1525) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% in the galantamine-treated patients included nausea (225, 7.7%), vomiting (119, 4.1%), decreased appetite (56, 1.9%), dizziness (48, 1.6%), diarrhea (27, 0.9%), headache (26, 0.9%), decreased weight (24, 0.8%), and abdominal pain (15, 0.5%). Those events with an incidence of ≥ 0.5% in placebo patients included nausea (14, 0.9%) and dizziness (8, 0.5%).

In the 5 open-label studies, 103 (7.1%) patients (N=1454) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% included nausea (43, 3.0%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), decreased weight (9, 0.6%), dizziness (8, 0.6%), and diarrhea (7, 0.5%).

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of RAZADYNE® ER and RAZADYNE® . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Immune System Disorders: Hypersensitivity

Psychiatric Disorders: Hallucinations

Nervous System Disorders: Seizures

Ear and Labyrinth Disorders: Tinnitus

Vascular Disorders: Hypertension

Hepatobiliary Disorders: Hepatitis, increased hepatic enzyme

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme

Read the Razadyne ER (galantamine hbr er) Side Effects Center for a complete guide to possible side effects

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Interactions

Use With Anticholinergics

Galantamine has the potential to interfere with the activity of anticholinergic medications [see CLINICAL PHARMACOLOGY].

Use With Cholinomimetics And Other Cholinesterase Inhibitors

A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol [see CLINICAL PHARMACOLOGY].

Read the Razadyne ER Drug Interactions Center for a complete guide to possible interactions

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This monograph has been modified to include the generic and brand name in many instances.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Serious Skin Reactions

Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving RAZADYNE® ER and RAZADYNE® . Inform patients and caregivers that the use of RAZADYNE® ER or RAZADYNE® should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed and alternative therapy should be considered.

Anesthesia

Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.

Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities. Therefore, all patients should be considered at risk for adverse effects on cardiac conduction.

Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]).

Gastrointestinal Conditions

Through their primary action, cholinomimetics may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers, e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss. During therapy, the patient's weight should be monitored.

Genitourinary Conditions

Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions [see ADVERSE REACTIONS]. Seizure activity may also be a manifestation of Alzheimer's disease. Patients with Alzheimer's disease should be monitored closely for seizures while taking galantamine.

Pulmonary Conditions

Because of its cholinomimetic action, galantamine should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease. Respiratory function should be monitored closely for the occurrence of respiratory adverse effects.

Deaths In Subjects With Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in patients with mild cognitive impairment (MCI), a total of 13 patients on galantamine (n=1026) and 1 patient on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death).

Although the difference in mortality between galantamine-and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of galantamine. Specifically, in these two MCI studies, the mortality rate in the placebo-treated patients was markedly lower than the rate in placebo-treated patients in trials of galantamine in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the mortality rate in the galantamine-treated MCI patients was also lower than that observed in galantamine-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the galantamine group. Furthermore, in the MCI studies, no patients in the placebo group died after 6 months, a highly unexpected finding in this population.

Individuals with mild cognitive impairment demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically. RAZADYNE® ER and RAZADYNE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats, administration of galantamine (oral doses of 2, 8, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD of 24 mg/day) on a body surface area (mg/m²) basis. When galantamine (oral doses of 4, 12, 28, or 48 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m² basis. In a study in which pregnant rats were orally dosed with galantamine (2, 8, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre-and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD on a mg/m² basis.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RAZADYNE® ER and RAZADYNE® is administered to a nursing woman.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Seven double-blind, placebo-controlled clinical trials and 5 open-label trials in a total of 4474 patients have investigated RAZADYNE® ER and RAZADYNE® in the treatment of mild to moderate dementia of the Alzheimer's type [see ADVERSE REACTIONS and Clinical Studies]. The mean age of patients enrolled in these clinical studies was 75 years; 78% of these patients were between 65 and 84 years of age, and 11% of patients were 85 years of age or older.

Hepatic Impairment

In patients with moderate hepatic impairment, a dosage adjustment is recommended. The use of RAZADYNE® ER and RAZADYNE® in patients with severe hepatic impairment is not recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Renal Impairment

In patients with a creatinine clearance of 9 to 59 mL/min, a dosage adjustment is recommended. The use of RAZADYNE® ER and RAZADYNE® in patients with creatinine clearance less than 9 mL/min is not recommended [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

OverDose

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

As in any case of overdose, general supportive measures should be utilized. Signs and symptoms of significant overdosing of galantamine are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the following signs of cholinergic crisis may develop: severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

Tertiary anticholinergics such as atropine may be used as an antidote for RAZADYNE® ER and RAZADYNE® (galantamine hydrobromide) overdosage. Intravenous atropine sulfate titrated to effect is recommended at an initial dose of 0.5 to 1.0 mg i.v. with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics. It is not known whether galantamine and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included hypoactivity, tremors, clonic convulsions, salivation, lacrimation, chromodacryorrhea, mucoid feces, and dyspnea.

In one postmarketing report, one patient who had been taking 4 mg of galantamine daily for a week inadvertently ingested eight 4 mg tablets (32 mg total) on a single day. Subsequently, she developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness for which she required hospital treatment. Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalization. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 mL) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.

ContrainDications

RAZADYNE® ER and RAZADYNE® are contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation.

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism Of Action

Although the etiology of cognitive impairment in Alzheimer's disease (AD) is not fully understood, it has been reported that acetylcholine-producing neurons degenerate in the brains of patients with Alzheimer's disease. The degree of this cholinergic loss has been correlated with degree of cognitive impairment and density of amyloid plaques (a neuropathological hallmark of Alzheimer's disease).

Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process.

Pharmacokinetics

The pharmacokinetics of galantamine are linear over a dose range of 8-32 mg/day.

Absorption and Distribution

Galantamine is absorbed with time to peak concentration of about 1 hour. The absolute bioavailability of galantamine is about 90%. The bioavailability of the tablet formulation was the same as the bioavailability of the oral solution formulation. Food did not affect the AUC of galantamine, but Cmax was decreased by 25% and Tmax was delayed by 1.5 hours, when galantamine was administered with food. The mean volume of distribution of galantamine is 175 L.

The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.

Metabolism and Elimination

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.

In studies of oral 3H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93-99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.

After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20-25% of the total plasma clearance of about 300 mL/min. Galantamine has a terminal half-life of about 7 hours.

RAZADYNE® ER 24 mg extended-release capsules administered once daily under fasting conditions are bioequivalent to RAZADYNE® tablets 12 mg twice daily with respect to AUC24h and Cmin. The Cmax and Tmax of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with Cmax about 25% lower and median Tmax occurring about 4.5–5.0 hours after dosing. Dose-proportionality is observed for RAZADYNE® ER extended-release capsules over the dose range of 8 to 24 mg daily and steady state is achieved within a week. There was no effect of age on the pharmacokinetics of RAZADYNE® ER extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.

There are no appreciable differences in pharmacokinetic parameters when RAZADYNE® ER extended-release capsules are given with food compared to when they are given in the fasted state.

Specific Populations

Elderly

Data from clinical trials in patients with Alzheimer's disease indicate that galantamine concentrations are 30-40% higher in those patients than in healthy young subjects.

Gender and Race

A population pharmacokinetic analysis (on 539 men and 550 women) indicates that galantamine clearance is about 20% lower in women than in men (which is explained by a lower body weight in women) and that race (n=1029 White, 24 Black, 13 Asian and 23 other) did not affect the clearance of galantamine.

Hepatic Impairment

Following a single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n=8; Child-Pugh score of 5-6) were similar to the pharmacokinetics of galantamine in healthy subjects. In patients with moderate hepatic impairment (n=8; Child Pugh score of 7-9), galantamine clearance was decreased by about 25% compared to galantamine clearance in normal volunteers. Exposure to galantamine would be expected to increase further with increasing degree of hepatic impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Renal Impairment

Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in patients with moderate and severe renal impairment, respectively, compared with normal volunteers [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

CYP2D6 Poor Metabolizers

Approximately 7% of the normal population has a genetic variation that leads to reduced levels of activity of CYP2D6 isozyme. Such individuals have been referred to as poor metabolizers. After a single oral dose of 4 mg or 8 mg galantamine, CYP2D6 poor metabolizers demonstrated a similar Cmax and about 35% AUC∞ increase of unchanged galantamine compared to extensive metabolizers.

A total of 356 patients with Alzheimer's disease enrolled in two Phase 3 studies were genotyped with respect to CYP2D6 (n=210 hetero-extensive metabolizers, 126 homo-extensive metabolizers, and 20 poor metabolizers).Population pharmacokinetic analysis indicated that there was a 25% decrease in median clearance in poor metabolizers compared to extensive metabolizers. Dosage adjustment is not necessary in patients identified as poor metabolizers as the dose of drug is individually titrated to tolerability.

Drug-Drug Interactions

Multiple metabolic pathways and renal excretion are involved in the elimination of galantamine so no single pathway appears predominant. Based on in vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved in the metabolism of galantamine. CYP2D6 was involved in the formation of O-desmethyl-galantamine, whereas CYP3A4 mediated the formation of galantamine-N-oxide. Galantamine is also glucuronidated and excreted unchanged in urine.

Effect of Other Drugs on Galantamine
  • CYP3A4 Inhibitors:
    Ketoconazole
    Ketoconazole, a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6, when administered at a dose of 200 mg two times a day for 4 days, increased the AUC of galantamine by 30%.
    Erythromycin
    Erythromycin, a moderate inhibitor of CYP3A4, when administered at a dose of 500 mg four times a day for 4 days, affected the AUC of galantamine minimally (10% increase).
  • CYP2D6 Inhibitors:
    A population pharmacokinetics analysis on a database of 852 patients with Alzheimer's disease showed that the clearance of galantamine was reduced about 25-33% by the concurrent administration of amitriptyline (n=17), fluoxetine (n=48), fluvoxamine (n=14), and quinidine (n=7), all of which are known inhibitors of CYP2D6.
    Paroxetine
    Paroxetine, a strong inhibitor of CYP2D6, when administered at a dose of 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%.
  • H2 Antagonists
    Galantamine was administered as a single dose of 4 mg on Day 2 of a 3-day treatment with either cimetidine (800 mg daily) or ranitidine (300 mg daily). Cimetidine increased the bioavailability of galantamine by approximately 16%. Ranitidine had no effect on the pharmacokinetics of galantamine.
  • Memantine
    Memantine, an N-methyl-D-aspartate receptor antagonist, when administered at a dose of 10 mg two times a day, had no effect on the pharmacokinetics of galantamine (16 mg/day) at steady state.
Effect of Galantamine on Other Drugs
  • In Vitro Studies
    In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 or CYP2E1. This indicates that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low.
  • In Vivo Studies
    Warfarin
    Multiple doses of galantamine at 24 mg/day had no effect on the pharmacokinetics of R-and S-warfarin (administered in a single dose of 25 mg) or on the increased prothrombin time induced by warfarin. The protein binding of warfarin was unaffected by galantamine.
  • Digoxin
    Multiple doses of galantamine at 24 mg/day had no effect on the steady-state pharmacokinetics of digoxin (at a dose of 0.375 mg once daily) when those two drugs were co-administered. In that study, however, one healthy subject was hospitalized on account of 2nd and 3rd degree heart block and bradycardia.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In a 24-month oral carcinogenicity study in rats, an increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the MRHD of 24 mg/day on a mg/m² basis or 6 times on a plasma exposure [AUC] basis) and 30 mg/kg/day (12 times MRHD on a mg/m² basis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/m² basis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/m² and AUC basis).

Galantamine was not carcinogenic in a 6-month carcinogenicity study in transgenic (P 53-deficient) mice at oral doses up to 20 mg/kg/day, or in a 24-month carcinogenicity study in mice at oral doses up to 10 mg/kg/day (equivalent to the MRHD on a plasma AUC basis).

Mutagenesis

Galantamine was negative in a battery of in vitro (bacterial reverse mutation, mouse lymphoma tk, and chromosomal aberration in mammalian cells) and in vivo (mouse micronucleus) genotoxicity assays.

Impairment of Fertility

No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/m² basis) for 14 days prior to mating in females and for 60 days prior to mating in males.

Clinical Studies

The effectiveness of galantamine as a treatment for Alzheimer's disease is demonstrated by the results of 5 randomized, double-blind, placebo-controlled clinical investigations in patients with probable Alzheimer's disease, 4 with the immediate-release tablet and 1 with the extended-release capsule [diagnosed by NINCDS-ADRDA criteria, with Mini-Mental State Examination scores that were ≥ 10 and ≤ 24]. Doses studied with the tablet formulation were 8-32 mg/day given as twice daily doses. In 3 of the 4 studies with the tablet, patients were started on a low dose of 8 mg, then titrated weekly by 8 mg/day to 24 or 32 mg as assigned. In the fourth study (USA 4-week Dose Escalation Fixed-Dose Study) dose escalation of 8 mg/day occurred over 4-week intervals. The mean age of patients participating in these 4 galantamine trials was 75 years with a range of 41 to 100. Approximately 62% of patients were women and 38% were men. The racial distribution was White 94%, Black 3% and other races 3%. Two other studies examined a three times daily dosing regimen; these also showed or suggested benefit but did not suggest an advantage over twice daily dosing.

Study Outcome Measures

In each study, the primary effectiveness of galantamine was evaluated using a dual outcome assessment strategy as measured by the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Impression of Change that required the use of caregiver information (CIBIC-plus).

The ability of galantamine to improve cognitive performance was assessed with the cognitive sub-scale of the Alzheimer's Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The patients recruited as participants in each study using the tablet formulation had mean scores on ADAS-cog of approximately 27 units, with a range from 5 to 69. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggests that they gain 6 to 12 units a year on the ADAS-cog. Lesser degrees of change, however, are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in galantamine trials was approximately 4.5 units per year.

The ability of galantamine to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-plus evaluations from other clinical trials. The CIBIC-plus used in the trials was a semi-structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of 4 major areas of patient function: general, cognitive, behavioral and activities of daily living. It represents the assessment of a skilled clinician based on his/her observation at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

Immediate-Release Tablets

U.S. Twenty-One Week Fixed-Dose Study

In a study of 21 weeks duration, 978 patients were randomized to doses of 8, 16, or 24 mg of galantamine per day, or to placebo, each given in 2 divided doses. Treatment was initiated at 8 mg/day for all patients randomized to galantamine, and increased by 8 mg/day every 4 weeks. Therefore, the maximum titration phase was 8 weeks and the minimum maintenance phase was 13 weeks (in patients randomized to 24 mg/day of galantamine).

Effects on the ADAS-cog

Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all four dose groups over the 21 weeks of the study. At 21 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 1.7, 3.3, and 3.6 units for the 8, 16 and 24 mg/day treatments, respectively. The 16 mg/day and 24 mg/day treatments were statistically significantly superior to placebo and to the 8 mg/day treatment. There was no statistically significant difference between the 16 mg/day and 24 mg/day dose groups.

Figure 1: Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 21 Weeks (5 Months) of Treatment

Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 21 Weeks (5 Months) of Treatment - Illustration

Figure 2 illustrates the cumulative percentages of patients from each of the four treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvements.

Figure 2: Cumulative Percentage of Patients Completing 21 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores. The Percentages of Randomized Patients Who Completed the Study Were: Placebo 84%, 8 mg/day 77%, 16 mg/day 78% and 24 mg/day 78%.

Cumulative Percentage of Patients Completing 21 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores - Illustration

 

Treatment Change in ADAS-cog
-10 -7 -4 -0
Placebo 3.6% 7.6% 19.6 % 41.8%
8 mg/day 5.9% 13.9% 25.7% 46.5%
16 mg/day 7.2% 15.9% 35.6% 65.4%
24 mg/day 10.4% 22.3% 37.0% 64.9%
Effects on the CIBIC-plus

Figure 3 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the four treatment groups who completed 21 weeks of treatment. The galantamine-placebo differences for these groups of patients in mean rating were 0.15, 0.41 and 0.44 units for the 8, 16 and 24 mg/day treatments, respectively. The 16 mg/day and 24 mg/day treatments were statistically significantly superior to placebo. The differences vs. the 8 mg/day treatment for the 16 and 24 mg/day treatments were 0.26 and 0.29, respectively. There were no statistically significant differences between the 16 mg/day and 24 mg/day dose groups.

Figure 3: Distribution of CIBIC-plus Ratings at Week 21

Distribution of CIBIC-plus Ratings at Week 21 - Illustration
U.S. Twenty-Six Week Fixed-Dose Study

In a study of 26 weeks duration, 636 patients were randomized to either a dose of 24 mg or 32 mg of galantamine per day, or to placebo, each given in two divided doses. The 26-week study was divided into a 3-week dose titration phase and a 23-week maintenance phase.

Effects on the ADAS-cog

Figure 4 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 3.9 and 3.8 units for the 24 mg/day and 32 mg/day treatments, respectively. Both treatments were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 4: Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment

Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment - Illustration

Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon, or shifted to the right of the curve for placebo, respectively.

 

Treatment Change in ADAS-cog
-10 -7 -4 -0
Placebo 2.1% 5.7% 16.6 % 43.9%
24 mg/day 7.6% 18.3% 33.6% 64.1%
32 mg/day 11.1% 19.7% 33.3% 58.1%

Figure 5: Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores. The Percentages of Randomized Patients Who Completed the Study Were: Placebo 81%, 24 mg/day 68%, and 32 mg/day 58%.

Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores - Illustration
Effects on the CIBIC-plus

Figure 6 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 26 weeks of treatment. The mean galantamine-placebo differences for these groups of patients in the mean rating were 0.28 and 0.29 units for 24 and 32 mg/day of galantamine, respectively. The mean ratings for both groups were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 6: Distribution of CIBIC-plus Ratings at Week 26

Distribution of CIBIC-plus Ratings at Week 26 - Illustration
International Twenty-Six Week Fixed-Dose Study

In a study of 26 weeks duration identical in design to the USA 26-Week Fixed-Dose Study, 653 patients were randomized to either a dose of 24 mg or 32 mg of galantamine per day, or to placebo, each given in two divided doses. The 26-week study was divided into a 3-week dose titration phase and a 23-week maintenance phase.

Effects on the ADAS-cog

Figure 7 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 3.1 and 4.1 units for the 24 mg/day and 32 mg/day treatments, respectively. Both treatments were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 7: Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment

Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment - Illustration

Figure 8 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvements.

Figure 8: Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores. The Percentages of Randomized Patients Who Completed the Study Were: Placebo 87%, 24 mg/day 80%, and 32 mg/day 75%.

Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores - Illustration

 

Treatment Change in ADAS-cog
-10 -7 -4 -0
Placebo 1.2% 5.8% 15.2 % 39.8%
24 mg/day 4.5% 15.4% 30.8% 65.4%
32 mg/day 7.9% 19.7% 34.9% 63.8%
Effects on the CIBIC-plus

Figure 9 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 26 weeks of treatment. The mean galantamine-placebo differences for these groups of patients in the mean rating of change from baseline were 0.34 and 0.47 for 24 and 32 mg/day of galantamine respectively. The mean ratings for the galantamine groups were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 9: Distribution of CIBIC-plus Rating at Week 26

Distribution of CIBIC-plus Rating at Week 26 - Illustration
International Thirteen-Week Flexible-Dose Study

In a study of 13 weeks duration, 386 patients were randomized to either a flexible dose of 24-32 mg/day of galantamine or to placebo, each given in two divided doses. The 13-week study was divided into a 3-week dose titration phase and a 10-week maintenance phase. The patients in the active treatment arm of the study were maintained at either 24 mg/day or 32 mg/day at the discretion of the investigator.

Effects on the ADAS-cog

Figure 10 illustrates the time course for the change from baseline in ADAS-cog scores for both dose groups over the 13 weeks of the study. At 13 weeks of treatment, the mean difference in the ADAS-cog change scores for the treated patients compared to the patients on placebo was 1.9. Galantamine at a dose of 24-32 mg/day was statistically significantly superior to placebo.

Figure 10: Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 13 Weeks of Treatment

Time-Course of the Change From Baseline in ADAS-cog Score for Patients Completing 13 Weeks of Treatment - Illustration

Figure 11 illustrates the cumulative percentages of patients from each of the two treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine group is more likely to show the greater improvement.

Figure 11: Cumulative Percentage of Patients Completing 13 Weeks of Double-Blind Treatment With Specified Changes from Baseline in ADAS-cog Scores. The Percentages of Randomized Patients Who Completed the Study Were: Placebo 90%, 24-32 mg/day 67%.

Cumulative Percentage of Patients Completing 13 Weeks of Double-Blind Treatment With Specified Changes from Baseline in ADAS-cog Scores - Illustration

 

Treatment Change in ADAS-cog
-10 -7 -4 -0
Placebo 1.9% 5.6% 19.4 % 50.0%
24 or 32 mg/day 7.1% 18.8% 32.9% 65.3%
Effects on the CIBIC-plus

Figure 12 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the two treatment groups who completed 13 weeks of treatment. The mean galantamine-placebo differences for the group of patients in the mean rating of change from baseline were 0.37 units. The mean rating for the 24–32 mg/day group was statistically significantly superior to placebo.

Figure 12: Distribution of CIBIC-plus Ratings at Week 13

Distribution of CIBIC-plus Ratings at Week 13 -  Illustration
Age, Gender and Race

Patient's age, gender, or race did not predict clinical outcome of treatment.

Extended-Release Capsules

The efficacy of galantamine extended-release capsules was studied in a randomized, double-blind, placebo-controlled trial which was 6 months in duration, and had an initial 4-week dose-escalation phase. In this trial, patients were assigned to one of 3 treatment groups: Galantamine extended-release capsules in a flexible dose of 16 to 24 mg once daily; galantamine tablets in a flexible dose of 8 to 12 mg twice daily; and placebo. The primary efficacy measures in this study were the ADAS-cog and CIBIC-plus. On the protocol-specified primary efficacy analysis at Month 6, a statistically significant improvement favoring galantamine extended-release capsules over placebo was seen for the ADAS-cog, but not for the CIBIC-plus. Galantamine extended-release capsules showed a statistically significant improvement when compared with placebo on the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, a measure of function, and a secondary efficacy measure in this study. The effects of both galantamine extended-release capsules and galantamine tablets on the ADAS-cog, CIBIC-plus, and ADCS-ADL were similar in this study.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

General Dosing Guidance

Caregivers should be instructed about the recommended dosage and administration of RAZADYNE® ER and RAZADYNE® (galantamine hydrobromide). RAZADYNE® ER Extended-Release Capsules should be administered once daily in the morning, preferably with food. RAZADYNE® Tablets and Oral Solution should be administered twice per day, preferably with the morning and evening meals. Dose escalation (dose increases) should follow a minimum of four weeks at prior dose. If therapy has been interrupted for more than three days, the patient should be restarted with the lowest dose and then re-titrated to an appropriate dosage [see DOSAGE AND ADMINISTRATION].

Patients and caregivers should be advised to ensure adequate fluid intake during treatment [see DOSAGE AND ADMINISTRATION].

Patients and caregivers should be advised that the most frequent adverse events associated with use of the drug can be minimized by following the recommended dosage and administration.

Oral Solution Instruction Sheet

Caregivers should be instructed in the correct procedure for administering RAZADYNE® Oral Solution. In addition, they should be informed of the existence of an Instruction Sheet (included with the product) describing how the solution is to be administered. They should be urged to read this sheet prior to administering RAZADYNE® Oral Solution. Caregivers should direct questions about the administration of the solution to either their physician or pharmacist.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

GALANTAMINE EXTENDED-RELEASE CAPSULE - ORAL

 

(ga-LAN-tuh-meen)

 

COMMON BRAND NAME(S): Razadyne ER

 

USES: Galantamine is used to treat mild to moderate confusion (dementia) related to Alzheimer's disease. It does not cure Alzheimer's disease, but it may improve memory, awareness, and the ability to perform daily functions. This medication works by restoring the balance of certain natural substances (neurotransmitters) in the brain.

 

HOW TO USE: Take this medication by mouth with food, usually once daily in the morning with breakfast or as directed by your doctor. This medication may be taken on an empty stomach if necessary. Drink plenty of fluids with this medication unless instructed otherwise. To lower your risk of side effects, your dosage will be gradually increased to your target dose. Your dosage is based on your medical condition and response to therapy. Do not take more than the maximum recommended dose of 24 milligrams per day.

Swallow the capsules whole. Do not crush or chew the capsules. Doing so can destroy the long action of the drug and may increase side effects.

If you stop taking galantamine for several days, consult your doctor or pharmacist before restarting it. Your dosage should be reduced to lower the risk of side effects. Your dosage should then be increased gradually. Follow all your doctor's dosing instructions exactly.

Use this medication regularly in order to get the most benefit from it. Do not stop taking it or increase the dosage unless your doctor instructs you to do so.

It may take at least 4 weeks of continued use before the full benefit of this drug takes effect.

Inform your doctor if your condition worsens.

Consumer Overview Side Effect

SIDE EFFECTS: Nausea, vomiting, diarrhea, dizziness, drowsiness, loss of appetite, and weight loss may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: fainting, unusually slow heartbeat, difficult urination.

Get medical help right away if you have any very serious side effects, including: seizures, black/bloody stools, vomit that looks bloody or like coffee grounds, severe stomach/abdominal pain, irregular heartbeat.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Razadyne ER (galantamine hbr er) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before taking galantamine, tell your doctor or pharmacist if you are allergic to it; or to daffodil plants; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe liver disease, severe kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, kidney problems, stomach/intestinal problems (e.g., ulcers, bleeding), heart problems (e.g., sick sinus syndrome, bradycardia, AV block, arrhythmias), breathing/lung problems (e.g., severe asthma, COPD-chronic obstructive pulmonary disease), seizures, problems urinating (e.g., due to enlarged prostate).

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are taking this medication.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is unknown if this drug passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anticholinergic drugs (e.g., atropine, benztropine, diphenhydramine, scopolamine, tolterodine), aspirin (high doses used for arthritis), cholinergic drugs (e.g., bethanechol), cholinesterase inhibitors (e.g., neostigmine), long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen), drugs affecting liver enzymes that remove galantamine from your body (such as azole antifungals including ketoconazole, amitriptyline, SSRI antidepressants including paroxetine, quinidine).

Also report the use of heart drugs (those that decrease heart rate or block AV impulse conduction) such as: beta-blockers (e.g., metoprolol, propranolol), calcium channel blockers (e.g., diltiazem, verapamil), digoxin.

Check all prescription and nonprescription medicine labels carefully since many medications contain pain relievers/fever reducers (NSAIDs such as aspirin, ibuprofen, or naproxen) which, if taken together with galantamine, may increase your risk for stomach/intestinal bleeding. Low-dose aspirin, as prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually at dosages of 81-325 milligrams per day), should be continued. Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include muscle weakness or twitching, severe stomach cramping, slow or shallow breathing, slow/fast/irregular heartbeat, fainting, and seizures.

 

NOTES: Do not share this medication with others.

Since galantamine may cause loss of appetite and weight loss, your doctor should monitor your weight before and during treatment with this medication.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

Information last revised November 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Razadyne, Razadyne ER

Generic Name: galantamine (Pronunciation: ga LAN ta meen)

  • What is galantamine (Razadyne ER)?
  • What are the possible side effects of galantamine (Razadyne ER)?
  • What is the most important information I should know about galantamine (Razadyne ER)?
  • What should I discuss with my healthcare provider before taking galantamine (Razadyne ER)?
  • How should I take galantamine (Razadyne ER)?
  • What happens if I miss a dose (Razadyne ER)?
  • What happens if I overdose (Razadyne ER)?
  • What should I avoid while taking galantamine (Razadyne ER)?
  • What other drugs will affect galantamine (Razadyne ER)?
  • Where can I get more information?

What is galantamine (Razadyne ER)?

Galantamine improves the function of nerve cells in the brain. It works by preventing the breakdown of a chemical called acetylcholine (ah see til KO leen). People with dementia usually have lower levels of this chemical, which is important for the processes of memory, thinking, and reasoning.

Galantamine is used to treat mild to moderate dementia caused by Alzheimer's disease.

Galantamine may also be used for purposes not listed in this medication guide.

Razadyne 12 mg

round, brown, imprinted with G 12, JANSSEN

What are the possible side effects of galantamine (Razadyne ER)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using galantamine and call your doctor at once if you have a serious side effect such as:

  • chest pain, slow heart rate;
  • feeling like you might pass out;
  • blood in your urine or stool;
  • coughing up blood or vomit that looks like coffee grounds;
  • painful or difficult urination;
  • urinating less than usual or not at all;
  • weakness, confusion, decreased sweating, extreme thirst, hot dry skin; or
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • feeling tired, dizzy, or drowsy;
  • headache, blurred vision, runny nose;
  • depression, sleep problems (insomnia);
  • nausea, vomiting, stomach pain, loss of appetite;
  • weight loss; or
  • unusual or unpleasant taste in your mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Razadyne ER (galantamine hbr er) Side Effects Center for a complete guide to possible side effects

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What is the most important information I should know about galantamine (Razadyne ER)?

Before taking galantamine, tell your doctor if you have urination problems, heart disease, a heart rhythm disorder, stomach ulcers or bleeding, a seizure disorder, kidney disease, liver disease, or asthma.

Stop using galantamine and call your doctor at once if you have chest pain, slow heart rate, blood in your stools, coughing up blood, decreased urination, weakness, confusion, extreme thirst, or hot, dry skin.

There are many other drugs that can interact with galantamine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

If you need surgery, tell the surgeon ahead of time that you are using galantamine. You may need to stop using the medicine for a short time.

If you have stopped taking galantamine for any reason, talk with your doctor before you start taking it again. You may need to restart the medication at a lower dose.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Side Effects Centers
  • Razadyne ER

Patient Detailed How Take

What should I discuss with my healthcare provider before taking galantamine (Razadyne ER)?

You should not use galantamine if you are allergic to it.

To make sure you can safely take galantamine, tell your doctor if you have any of these other conditions:

  • urination problems;
  • heart disease or a heart rhythm disorder;
  • a history of stomach ulcer or bleeding;
  • seizures or epilepsy;
  • kidney disease;
  • liver disease; or
  • a history of asthma or chronic obstructive pulmonary disease (COPD).

FDA pregnancy category B. Galantamine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether galantamine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take galantamine (Razadyne ER)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

The galantamine extended-release capsule is usually taken once per day in the morning. Follow your doctor's instructions.

The galantamine short-acting tablet or the oral solution (liquid) are usually given two times per day, with meals. Follow your doctor's instructions.

The extended-release capsule works best if you take it with food.

Do not crush, chew, break, or open an extended-release capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

Measure the liquid using only the special dose-measuring device provided. Empty the medicine into 3 to 4 ounces of any non-alcoholic beverage. Stir this mixture and drink all of it right away. Rinse the dose-measuring device with water after each use.

The liquid form of this medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Take galantamine with a full glass of water. Drink 6 to 8 full glasses of water each day to keep from getting dehydrated while taking this medication.

If you need surgery, tell the surgeon ahead of time that you are using galantamine. You may need to stop using the medicine for a short time.

If you have stopped taking galantamine for any reason, talk with your doctor before you start taking it again. You may need to restart the medication at a lower dose.

Store at room temperature away from moisture and heat. Do not allow the liquid medicine to freeze.

Side Effects Centers
  • Razadyne ER

Patient Detailed Avoid Taking

What happens if I miss a dose (Razadyne ER)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Razadyne ER)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe nausea, vomiting, stomach cramps, muscle weakness or spasm, watery eyes, drooling, increased urination or bowel movements, sweating, slow heart rate, feeling light-headed or fainting, and seizure (convulsions).

What should I avoid while taking galantamine (Razadyne ER)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect galantamine (Razadyne ER)?

Tell your doctor about all other medicines you use, especially:

  • donepezil (Aricept);
  • erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole);
  • ketoconazole (Nizoral);
  • paroxetine (Paxil);
  • rivastigmine (Exelon);
  • atropine (Atreza, Sal-Tropine), belladonna (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm Scop);
  • bladder or urinary medicines such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);
  • bronchodilators such as ipratropium (Atrovent) or tiotropium (Spiriva);
  • irritable bowel medicines such as dicyclomine (Bentyl), hyoscyamine (Hyomax), or propantheline (Pro-Banthine);
  • NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or
  • ulcer medications such as glycopyrrolate (Robinul) or mepenzolate (Cantil).

This list is not complete and there are many other drugs that can interact with galantamine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Where can I get more information?

Your pharmacist can provide more information about galantamine.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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