گالانتامین
Galantamine HBr ER (Razadyne ER)
گالانتامین

نام ژنریک

Galantamine

شکل دارویی

اشكال دارويي:


Tablet: 4, 8, 12mg


Capsule, Extended Release: 8, 16, 24mg


Solution: 20 mg/5ml

موارد مصرف

موارد و مقدار مصرف


دمانس خفيف تا متوسط از نوع آلزايمر.


بزرگسالان: شروع با 4 ميلي گرم دوبار در روز ترجيحا با وعده غذاي صبحانه و عصرانه. اگر پس از حداقل 4 هفته از درمان، دوزاژ دارو خوب تحمل شد، مقدار مصرف را به 8 ميلي گرم دو بار در روز افزايش دهيد. پس از گذشت حداقل 4 هفته از دوز قبلي، مي‌توان دوز 12 ميلي‌گرم دو بار در هفته را امتحان کرد. مقدار مصرف پيشنهادي روزانه 16 تا 24 ميلي گرم در دو دوز منقسم مي‌باشد؛ اگر از فرم ER استفاده شود، 8 ميلي گرم خوراکي يک بار در روز با صبحانه، پس از حداقل 4 هفته به 16 ميلي‌گرم خوراکي يک بار در روز افزايش مي‌يابد. اين دوز پس از حداقل 4 هفته ديگر، بر اساس پاسخ و مقدار تحمل بيمار، به 24 ميلي گرم يک بار در روز قابل افزايش است.


مقدار مصرف در نارسايي کليه و کبد: در نارسايي متوسط عملکرد کبد (child- pugh score= 7-9)، دوز روزانه نبايد از 16 ميلي گرم بيشتر باشد.


دوز تنظيم شده 16 ميلي گرم در روز براي هر دو مدل فرمولاسيون مي‌باشد (conventional و ER). در نارسايي شديد عملکرد کبد
(child- pugh score=10-15) مصرف دارو توصيه نمي‌شود. در نارسايي متوسط کليه، مقدار مصرف روزانه از 16 ميلي گرم بيشتر نشود. در کليرانس کراتينين کمتر از ml/min 9 مصرف دارو توصيه نمي‌شود.


مكانيسم اثر


اثر کولينوميمتيک: مکانيسم دقيق اين عمل ناشناخته مي‌باشد. اين دارو يک مهار کننده رقابتي و برگشت پذير استيل کولين استراز مي‌باشد و به نظر مي‌رسد که عملکرد کولينرژيک را از طريق افزايش سطح استيل کولين در مغز تقويت مي‌کند.


فارماکوکينتيک


جذب: به خوبي و به سرعت جذب مي‌شود و زيست دستيابي آن حدود 90% مي‌باشد. سطح دارو در حدود يک ساعت به پيک خود مي‌رسد. در افراد مسن سطح دارو 30 تا 40% بالاتر از افراد جوان مي‌باشد.


پخش: به مقدار قابل توجهي در سلولهاي خون گسترش مي‌يابد. اتصال پروتئيني آن ناچيز است.


متابوليسم: در کبد توسط آنزيم CYP2D6 و CYP3A4 متابوليزه شده و گلوکورونيده مي‌شود. درمان همزمان با مهارکننده‌هاي اين سيستم آنزيمي مي‌تواند مقدار زيست دستيابي گالانتامين را افزايش دهد.


دفع: به صورت تغيير نيافته، گلوکورونيده و متابوليت درادرار ترشح مي‌شود. نيمه عمر دارو حدود 7 ساعت مي‌باشد.

موارد منع مصرف

اثر بر آزمايشهاي تشخيصي


اين دارو مي‌تواند سطح هموگلوبين و هماتوکريت را کاهش دهد.

موارد قابل توجه

-

تداخل دارویی

عوارض جانبي


اعصاب مرکزي: دپرسيون، گيجي، خستگي، سردرد، بي خوابي، خواب آلودگي، سنکوپ، ترمور.


قلبي - عروقي: براديکاردي.


چشم، گوش، حلق، بيني: رينيت.


دستگاه گوارش: درد شکمي، اسهال، بي اشتهايي، سوء هاضمه، تهوع، استفراغ.


ادراري - تناسلي: هماچوري، عفونت مجراي ادراري.


خون: آنمي.


متابوليک: کاهش وزن.


مسموميت و درمان


تظاهرات باليني: علائم مشابه کولينرژيک هاي ديگر؛ درگيري سيستم اعصاب مرکزي، سيستم عصبي پاراسمپاتيک و محل اتصال عصب به عضله. علاوه بر ضعف عضلاني يا فاسيکولاسيون، علائم کولينرژيک ديگر مانند تهوع شديد، استفراغ، کرامپ گوارشي، آبريزش دهان، اشک ريزي، دفع ادرار، دفع مدفوع، تعريق، براديکاردي، افت فشار خون، دپرسيون تنفسي، کلاپس و تشنج نيز مي‌تواند اتفاق بيفتد. ضعف عضلاني ممکن است افزايش يافته و در صورت درگيري عضلات تنفسي موجب مرگ شود.


درمان: به صورت اقدامات حمايتي و علامتي مي‌باشد. آتروپين وريدي مي‌تواند به صورت آنتي دوت گالانتامين استفاده شود. شروع با دوز 0.5 تا 1 ميلي گرم پيشنهاد مي‌شود و دوزهاي بعدي بر اساس پاسخهاي کلينيکي بيمار مصرف مي شود. ميزان حذف دارو با دياليز نامشخص مي‌باشد.

مکانیزم اثر

عوارض جانبي


اعصاب مرکزي: دپرسيون، گيجي، خستگي، سردرد، بي خوابي، خواب آلودگي، سنکوپ، ترمور.


قلبي - عروقي: براديکاردي.


چشم، گوش، حلق، بيني: رينيت.


دستگاه گوارش: درد شکمي، اسهال، بي اشتهايي، سوء هاضمه، تهوع، استفراغ.


ادراري - تناسلي: هماچوري، عفونت مجراي ادراري.


خون: آنمي.


متابوليک: کاهش وزن.


مسموميت و درمان


تظاهرات باليني: علائم مشابه کولينرژيک هاي ديگر؛ درگيري سيستم اعصاب مرکزي، سيستم عصبي پاراسمپاتيک و محل اتصال عصب به عضله. علاوه بر ضعف عضلاني يا فاسيکولاسيون، علائم کولينرژيک ديگر مانند تهوع شديد، استفراغ، کرامپ گوارشي، آبريزش دهان، اشک ريزي، دفع ادرار، دفع مدفوع، تعريق، براديکاردي، افت فشار خون، دپرسيون تنفسي، کلاپس و تشنج نيز مي‌تواند اتفاق بيفتد. ضعف عضلاني ممکن است افزايش يافته و در صورت درگيري عضلات تنفسي موجب مرگ شود.


درمان: به صورت اقدامات حمايتي و علامتي مي‌باشد. آتروپين وريدي مي‌تواند به صورت آنتي دوت گالانتامين استفاده شود. شروع با دوز 0.5 تا 1 ميلي گرم پيشنهاد مي‌شود و دوزهاي بعدي بر اساس پاسخهاي کلينيکي بيمار مصرف مي شود. ميزان حذف دارو با دياليز نامشخص مي‌باشد.

فارماكوكینتیك

تداخل دارويي


مصرف همزمان با داروهايي مانند آمي تريپتيلين، فلوکستين، فلوواکسامين و کينيدين کليرانس گالانتامين را کاهش مي‌دهد.


مي تواند فعاليت داروهاي آنتي کولينرژيک را آنتاگونيزه کند. بيماران را مونيتور کنيد.


استفاده همزمان با داروهاي کولينرژيک مانند بتانکول و سوکسينيل کولين، مي‌تواند اثر سينرژيستيک ايجاد کند. بهتر است قبل از جراحي هايي که براي بيهوشي در آنها از سوکسينيل کولين يا بلاک کننده‌هاي عصبي- عضلاني مشابه استفاده مي‌شود، از مصرف دارو خودداري شود.


داروهايي مانند سايمتيدين، اريترومايسين، کتوکونازول و پاروکستين مي‌توانند زيست دستيابي گالانتامين را افزايش دهند. بيمار را مونيتور کنيد.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: مهار کننده رقابتي و برگشت پذير استيل کولين استراز.


طبقه‌بندي درماني: کولينوميمتيک.


طبقه‌بندي مصرف در بارداري: رده B


نام‌هاي تجاري: Reminyl


ملاحظات اختصاصي


براديکاردي و بلاک قلبي در بيماران با يا بدون اختلالات هدايتي زمينه‌اي گزارش شده است. تمامي بيماران از نظر عوارض جانبي و اثر بر هدايت قلبي بررسي شوند.


جهت کاهش ريسک تهوع و استفراغ، دارو با غذا و ضد تهوع مصرف شده و بيمار مايعات کافي دريافت کند.


در صورت قطع مصرف دارو براي چند روز، دارو مجددا با حداقل دوز شروع شده و افزايش دوز براي رسيدن به مقدار مصرف قبلي، در فاصله‌هاي 4 هفته‌اي يا طولاني تر انجام شود.


محلول خوراکي و قرصهاي معمولي فراهمي زيستي يکسان دارند.


به علت خطر افزايش ترشح اسيد معده، بيماران، بويژه آنهايي که ريسک ايجاد زخمهاي گوارشي را دارند، از نظر علائم خونريزي فعال يا مخفي به دقت بررسي شوند.


نكات قابل توصيه به بيمار


قرصهاي معمولي با وعده غذاي صبحانه و عصرانه مصرف شود.


تهوع و استفراغ از عوارض جانبي شايع اين دارو مي‌باشد.


در صورت نحوه مصرف و دوزاژ صحيح دارو، ميزان عوارض جانبي دارو به حداقل مقدار خود مي‌رسد.


در صورت قطع مصرف دارو براي چند روز، دارو مجددا با حداقل دوز شروع شده و افزايش دوز بايد بر اساس برنامه انجام شود.


کاهش ضربان قلب به سرعت اطلاع داده شود.


اين دارو مي‌تواند عملکرد حافظه را بهبود بخشد، اما در مورد تغيير علائم بيماري کنوني ممکن است موفقيت چنداني نداشته باشد.


محلول خوراکي را مي‌توان با يک نوشيدني غير الکلي مخلوط کرده و بلافاصله مصرف کرد.


مصرف در كودكان: بي خطري و کارايي دارو در کودکان اثبات نشده است.


مصرف در شيردهي: ترشح دارو در شير نامشخص مي‌باشد. هيچ انديکاسيوني براي مصرف دارو در دوران شيردهي موجود نمي‌باشد.

Galantamine HBr ER (Razadyne ER)

RAZADYNE® ER
(galantamine HBr) Extended-Release Capsules

RAZADYNE®
(galantamine HBr) Tablets and Oral Solution

DRUG DESCRIPTION

RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide) is galantamine hydrobromide, a reversible, competitive acetylcholinesterase inhibitor. Galantamine hydrobromide is known chemically as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6Hbenzofuro[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® (galantamine hydrobromide) Structural Formula Illustration

RAZADYNE® ER is available in opaque hard gelatin extended-release capsules of 8 mg (white), 16 mg (pink), and 24 mg (caramel) containing galantamine hydrobromide, equivalent to respectively 8, 16 and 24 mg galantamine base. Inactive ingredients include gelatin, diethyl phthalate, ethylcellulose, hypromellose, polyethylene glycol, titanium dioxide and sugar spheres (sucrose and starch). The 16 mg capsule also contains red ferric oxide. The 24 mg capsule also contains red ferric oxide and yellow ferric oxide.

RAZADYNE® for oral use is available in circular biconvex film-coated immediate-release tablets of 4 mg (off-white), 8 mg (pink), and 12 mg (orange-brown). Each 4, 8, and 12 mg (base equivalent) tablet contains 5.126, 10.253, 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® is also available as a 4 mg/mL oral solution. The inactive ingredients for this solution are methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium saccharin, sodium hydroxide and purified water.

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 any of these serious side effects:

  • chest pain, slow heart rate;
  • black, bloody, or tarry stools;
  • coughing up blood or vomit that looks like coffee grounds;
  • weakness, confusion, decreased sweating, extreme thirst, hot dry skin; or
  • urinating less than usual or not at all.

Less serious side...

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 »

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide) is indicated for the treatment of mild to moderate dementia of the Alzheimer's type.

DOSAGE AND ADMINISTRATION

RAZADYNE® ER Extended-Release Capsules

The dosage of RAZADYNE® ER (galantamine hydrobromide) Extended-Release Capsules shown to be effective in a controlled clinical trial is 16-24mg/day.

The recommended starting dose of RAZADYNE® ER is 8 mg/day. The dose 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. Dose increases should be based upon assessment of clinical benefit and tolerability of the previous dose.

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

Patients currently being treated with RAZADYNE® tablets can convert to RAZADYNE® ER by taking their last dose of RAZADYNE® tablets 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 dose.

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 dose of 32 mg/day is less well tolerated than lower doses and does not provide increased effectiveness, the recommended dose range is 16-24 mg/day given in a BID regimen. The dose of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dose of 24 mg of RAZADYNE® might provide additional benefit for some patients.

The recommended starting dose of RAZADYNE® Tablets and Oral Solution is 4 mg twice a day (8 mg/day). The dose should be increased to the initial maintenance dose 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). Dose 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 several days or longer, the patient should be restarted at the lowest dose and the dose escalated to the current dose.

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.

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

Doses in Special Populations

Galantamine plasma concentrations may be increased in patients with moderate to severe hepatic impairment. In patients with moderately impaired hepatic function (Child-Pugh score of 7-9), the total daily dose should generally not exceed 16 mg/day. The use of RAZADYNE® ER/RAZADYNE® in patients with severe hepatic impairment (Child-Pugh score of 10-15) is not recommended.

For patients with moderate renal impairment the dose should generally not exceed 16 mg/day. In patients with severe renal impairment (creatinine clearance < 9 mL/min), the use of RAZADYNE® ER/RAZADYNE® is not recommended.

HOW SUPPLIED

RAZADYNE® ER (galantamine hydrobromide) Extended-Release Capsules contain white to off-white pellets.

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

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

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

The capsules are supplied as follows:

8 mg capsules – bottles of 30 NDC 50458-387-30
16 mg capsules – bottles of 30 NDC 50458-388-30
24 mg capsules – bottles of 30 NDC 50458-389-30

RAZADYNE® Tablets are imprinted “JANSSEN” on one side, and “G” and the strength “4”, “8”, or “12” on the other.

4 mg off-white tablet: bottles of 60 NDC 50458-396-60
8 mg pink tablet: bottles of 60 NDC 50458-397-60
12 mg orange-brown tablet: bottles of 60 NDC 50458-398-60

RAZADYNE® 4 mg/mL oral solution (NDC 50458-490-10) 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.

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 (5986°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.

RAZADYNE® ER Extended-Release Capsules and RAZADYNE® Tablets are manufactured by: JOLLC, Gurabo, Puerto Rico. RAZADYNE® Oral Solution is manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium. RAZADYNE® ER Extended-Release Capsules and RAZADYNE® Tablets and Oral Solution are distributed by: Ortho-McNeil Neurologics, Inc. Titusville, NJ 08560. Revised April 2007

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Pre-Marketing Clinical Trial Experience

The specific adverse event data described in this section are based on studies of the immediate-release tablet formulation. In clinical trials, once-daily treatment with RAZADYNE® ER (galantamine hydrobromide) Extended-Release Capsules was well tolerated and adverse events were similar to those seen with RAZADYNE® Tablets.

Adverse Events Leading to Discontinuation

In two large scale, placebo-controlled trials of 6 months duration in which patients were titrated weekly from 8 to 16 to 24, and to 32 mg/day, the risk of discontinuation because of an adverse event in the galantamine group exceeded that in the placebo group by about threefold. In contrast, in a 5-month trial with escalation of the dose by 8 mg/day every 4 weeks, the overall risk of discontinuation because of an adverse event was 7%, 7%, and 10% for the placebo, galantamine 16 mg/day, and galantamine 24 mg/day groups, respectively, with gastrointestinal adverse effects the principle reason for discontinuing galantamine. Table 1 shows the most frequent adverse events leading to discontinuation in this study.

Table 1: Most Frequent Adverse Events Leading to Discontinuation in a Placebo-Controlled, Double-Blind Trial With a 4-Week Dose Escalation Schedule

Adverse Event 4-Week Escalation
Placebo
N=286
16 mg/day
N=279
24 mg/day
N=273
Nausea < 1% 2% 4%
Vomiting 0% 1% 3%
Anorexia < 1% 1% < 1%
Dizziness < 1% 2% 1%
Syncope 0% 0% 1%

Adverse Events Reported in Controlled Trials

The reported adverse events in trials using RAZADYNE® (galantamine hydrobromide) Tablets reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ.

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

Administration of RAZADYNE® with food, the use of anti-emetic medication, and ensuring adequate fluid intake may reduce the impact of these events.

The most frequent adverse events, defined as those occurring at a frequency of at least 5% and at least twice the rate on placebo with the recommended maintenance dose of either 16 or 24 mg/day of RAZADYNE® under conditions of every 4-week dose-escalation for each dose increment of 8 mg/day, are shown in Table 2. These events were primarily gastrointestinal and tended to be less frequent with the 16 mg/day recommended initial maintenance dose.

Table 2: The Most Frequent Adverse Events in the Placebo-Controlled Trial With Dose Escalation Every 4 Weeks Occurring in at Least 5% of Patients Receiving RAZADYNE® and at Least Twice the Rate on Placebo.

Adverse Event Placebo
N=286
RAZADYNE® 16 mg/day
N=279
RAZADYNE® 24 mg/day
N=273
Nausea 5% 13% 17%
Vomiting 1% 6% 10%
Diarrhea 6% 12% 6%
Anorexia 3% 7% 9%
Weight decrease 1% 5% 5%

Table 3: The most common adverse events (adverse events occurring with an incidence of at least 2% with RAZADYNE® treatment and in which the incidence was greater than with placebo treatment) are listed in Table 3 for four placebo-controlled trials for patients treated with 16 or 24 mg/day of RAZADYNE® .

Table 3: Adverse Events Reported in at Least 2% of Patients With Alzheimer's Disease Administered RAZADYNE® and at a Frequency Greater Than With Placebo

Body System
Adverse Event
Placebo
(N=801)
RAZADYNE®1
(N=1040)
Body as a whole - general disorders
  Fatigue 3% 5%
  Syncope 1% 2%
Central & peripheral nervous system disorders
  Dizziness 6% 9%
  Headache 5% 8%
  Tremor 2% 3%
Gastrointestinal system disorders
  Nausea 9% 24%
  Vomiting 4% 13%
  Diarrhea 7% 9%
  Abdominal pain 4% 5%
  Dyspepsia 2% 5%
Heart rate and rhythm disorders
  Bradycardia 1% 2%
Metabolic and nutritional disorders
  Weight decrease 2% 7%
Psychiatric disorders
  Anorexia 3% 9%
  Depression 5% 7%
  Insomnia 4% 5%
  Somnolence 3% 4%
Red blood cell disorders
  Anemia 2% 3%
Respiratory system disorders
  Rhinitis 3% 4%
Urinary system disorders
  Urinary tract infection 7% 8%
  Hematuria 2% 3%
1Adverse events in patients treated with 16 or 24 mg/day of RAZADYNE® in four placebo-controlled trials are included

Adverse events occurring with an incidence of at least 2% in placebo-treated patients that was either equal to or greater than with RAZADYNE® treatment were constipation, agitation, confusion, anxiety, hallucination, injury, back pain, peripheral edema, asthenia, chest pain, urinary incontinence, upper respiratory tract infection, bronchitis, coughing, hypertension, fall, and purpura.

There were no important differences in adverse event rates related to dose or sex. There were too few non-Caucasian patients to assess the effects of race on adverse event rates.

No clinically relevant abnormalities in laboratory values were observed.

Other Adverse Events Observed During Clinical Trials

RAZADYNE® Tablets were administered to 3055 patients with Alzheimer's disease. A total of 2357 patients received galantamine in placebo-controlled trials and 761 patients with Alzheimer's disease received galantamine 24 mg/day, the maximum recommended maintenance dose. About 1000 patients received galantamine for at least one year and approximately 200 patients received galantamine for two years.

To establish the rate of adverse events, data from all patients receiving any dose of galantamine in 8 placebo-controlled trials and 6 open-label extension trials were pooled. The methodology to gather and codify these adverse events was standardized across trials, using WHO terminology. All adverse events occurring in approximately 0.1% are included, except for those already listed elsewhere in labeling, WHO terms too general to be informative, or events unlikely to be drug caused. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients; rare adverse events - those occurring in fewer than 1/1000 patients. These adverse events are not necessarily related to RAZADYNE® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Additional adverse events observed in other clinical trials are also included below.

Body As a Whole – General Disorders: Frequent: chest pain, asthenia, fever, malaise

Cardiovascular System Disorders: Infrequent: postural hypotension, hypotension, dependent edema, cardiac failure, myocardial ischemia or infarction

Central & Peripheral Nervous System Disorders: Infrequent: vertigo, hypertonia, convulsions, involuntary muscle contractions, paresthesia, ataxia, hypokinesia, hyperkinesia, apraxia, aphasia, leg cramps, tinnitus, transient ischemic attack or cerebrovascular accident

Gastrointestinal System Disorders: Frequent: flatulence; Infrequent: gastritis, melena, dysphagia, rectal hemorrhage, dry mouth, saliva increased, diverticulitis, gastroenteritis, hiccup; Rare: esophageal perforation

Heart Rate & Rhythm Disorders: Infrequent: AV block, palpitation, atrial arrhythmias including atrial fibrillation and supraventricular tachycardia, QT prolonged, bundle branch block, T-wave inversion, ventricular tachycardia; Rare: severe bradycardia

Metabolic & Nutritional Disorders: Infrequent: hyperglycemia, alkaline phosphatase increased

Platelet, Bleeding & Clotting Disorders: Infrequent: purpura, epistaxis, thrombocytopenia

Psychiatric Disorders: Infrequent: apathy, paroniria, paranoid reaction, libido increased, delirium; Rare: suicidal ideation, suicide

Urinary System Disorders: Frequent: incontinence; Infrequent: hematuria, micturition frequency, cystitis, urinary retention, nocturia, renal calculi

Post-Marketing Experience

Other adverse events from post-approval controlled and uncontrolled clinical trials and post-marketing experience observed in patients treated with RAZADYNE® include:

Body as a Whole – General Disorders: dehydration (including rare, severe cases leading to renal insufficiency and renal failure)

Psychiatric Disorders: aggression

Gastrointestinal System Disorders: upper and lower GI bleeding

Hepatobiliary Disorders: elevated liver enzymes, hepatitis

Metabolic & Nutritional Disorders: hypokalemia

These adverse events may or may not be causally related to the drug.

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

DRUG INTERACTIONS

(see also CLINICAL PHARMACOLOGY, Drug-Drug Interactions)

Use with Anticholinergics

RAZADYNE® has the potential to interfere with the activity of anticholinergic medications.

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.

Effect of Other Drugs on Galantamine

In vitro

CYP3A4 and CYP2D6 are the major enzymes involved in the metabolism of galantamine. CYP3A4 mediates the formation of galantamine-N-oxide; CYP2D6 leads to the formation of Odesmethyl-galantamine. Because galantamine is also glucuronidated and excreted unchanged, no single pathway appears predominant.

In vivo

Cimetidine and Ranitidine: 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 PK of galantamine.

Ketoconazole: Ketoconazole, a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6, at a dose of 200 mg BID for 4 days, increased the AUC of galantamine by 30%.

Erythromycin: Erythromycin, a moderate inhibitor of CYP3A4 at a dose of 500 mg QID for 4 days, affected the AUC of galantamine minimally (10% increase).

Paroxetine: Paroxetine, a strong inhibitor of CYP2D6, at 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%.

Memantine: Memantine, an N-methyl-D-aspartate receptor antagonist, at a dose of 10 mg BID, had no effect on the pharmacokinetics of galantamine (16 mg/day) at steady state.

Effect of Galantamine on Other Drugs

In vitro

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

Warfarin: Galantamine at 24 mg/day had no effect on the pharmacokinetics of R- and S-warfarin (25 mg single dose) or on the prothrombin time. The protein binding of warfarin was unaffected by galantamine.

Digoxin: Galantamine at 24 mg/day had no effect on the steady-state pharmacokinetics of digoxin (0.375 mg once daily) when they were coadministered. In this study, however, one healthy subject was hospitalized for 2nd and 3rd degree heart block and bradycardia.

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

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. These actions may be particularly important to patients with supraventricular cardiac conduction disorders or to patients taking other drugs concomitantly that significantly slow heart rate. Postmarketing surveillance of marketed anticholinesterase inhibitors has shown, however, that 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.

In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation. The overall frequency of this event was 2-3% for galantamine doses up to 24 mg/day compared with < 1% for placebo. No increased incidence of heart block was observed at the recommended doses.

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 BID 0.4% [3/692]; 8 mg BID 1.3% [7/552]; 12 mg BID 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 RAZADYNE® (galantamine hydrobromide) have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

RAZADYNE® ER/RAZADYNE® , as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss (see ADVERSE REACTIONS).

Genitourinary

Although this was not observed in clinical trials with RAZADYNE® ER/RAZADYNE® , cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease. In clinical trials, there was no increase in the incidence of convulsions with RAZADYNE® ER/RAZADYNE® , compared to placebo.

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.

PRECAUTIONS

Deaths in Subjects with Mild Cognitive Impairment (MCI)

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

Although the difference in mortality between RAZADYNE® and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of RAZADYNE® . Specifically, in these two MCI studies, the mortality rate in the placebo-treated subjects was markedly lower than the rate in placebo-treated patients in trials of RAZADYNE® 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 RAZADYNE® -treated MCI subjects was also lower than that observed in RAZADYNE® -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 RAZADYNE® group. Furthermore, in the MCI studies, no subjects 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.

Special Populations

Hepatic Impairment

In patients with moderately impaired hepatic function, dose titration should proceed cautiously (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). The use of RAZADYNE® in patients with severe hepatic impairment is not recommended.

Renal Impairment

In patients with moderately impaired renal function, dose titration should proceed cautiously (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). In patients with severely impaired renal function (CLcr < 9 mL/min) the use of RAZADYNE® is not recommended.

Carcinogenesis, Mutagenesis and Impairment of Fertility

In a 24-month oral carcinogenicity study in rats, a slight increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the Maximum Recommended Human Dose [MRHD] on a mg/m2 basis or 6 times on an 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 oral carcinogenicity study in transgenic (P 53deficient) mice up to 20 mg/kg/day, or in a 24-month oral carcinogenicity study in male and female mice up to 10 mg/kg/day (2 times the MRHD on a mg/m2 basis and equivalent on an AUC basis).

Galantamine produced no evidence of genotoxic potential when evaluated in the in vitro Ames S. typhimurium or E. coli reverse mutation assay, in vitro mouse lymphoma assay, in vivo micronucleus test in mice, or in vitro chromosome aberration assay in Chinese hamster ovary cells.

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.

Pregnancy

Pregnancy Category B: In a study in which rats were dosed from day 14 (females) or day 60 (males) prior to mating through the period of organogenesis, a slightly increased incidence of skeletal variations was observed at doses of 8 mg/kg/day (3 times the Maximum Recommended Human Dose [MRHD] on a mg/m² basis) and 16 mg/kg/day. In a study in which pregnant rats were dosed from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at 8 and 16 mg/kg/day, but no adverse effects on other postnatal developmental parameters were seen. The doses causing the above effects in rats produced slight maternal toxicity. No major malformations were caused in rats given up to 16 mg/kg/day. No drug related teratogenic effects were observed in rabbits given up to 40 mg/kg/day (32 times the MRHD on a mg/m² basis) during the period of organogenesis.

There are no adequate and well-controlled studies of RAZADYNE® in pregnant women. RAZADYNE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether galantamine is excreted in human breast milk. RAZADYNE® has no indication for use in nursing mothers.

Pediatric Use

There are no adequate and well-controlled trials documenting the safety and efficacy of galantamine in any illness occurring in children. Therefore, use of RAZADYNE® in children is not recommended.

Last reviewed on RxList: 3/14/2012
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® (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 coadministered with quaternary anticholinergics. It is not known whether RAZADYNE® 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/RAZADYNE® (galantamine hydrobromide) is contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation.

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

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

Galantamine is well absorbed with absolute oral bioavailability of about 90%. It has a terminal elimination half-life of about 7 hours and pharmacokinetics are linear over the range of 8-32 mg/day.

The maximum inhibition of acetylcholinesterase activity of about 40% was achieved about one hour after a single oral dose of 8 mg galantamine in healthy male subjects.

Absorption and Distribution

Galantamine is rapidly and completely absorbed with time to peak concentration about 1 hour. Bioavailability of the tablet was the same as the bioavailability of an oral solution. Food did not affect the AUC of galantamine but Cmax decreased by 25% and Tmax was delayed by 1.5 hours. 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 (see PRECAUTIONS: DRUG INTERACTIONS). 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.

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.

Special 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.

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 those 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 normal volunteers. Exposure would be expected to increase further with increasing degree of hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment

Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in moderate and severely renal-impaired patients compared to normal volunteers (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Elderly

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

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of RAZADYNE® , but a population pharmacokinetic analysis indicates (n= 539 males and 550 females) that galantamine clearance is about 20% lower in females than in males (explained by lower body weight in females) and race (n= 1029 White, 24 Black, 13 Asian and 23 other) did not affect the clearance of RAZADYNE® .

Drug-Drug Interactions

(see also PRECAUTIONS: 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 the Metabolism of RAZADYNE®

Drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC of galantamine. Multiple dose pharmacokinetic studies demonstrated that the AUC of galantamine increased 30% and 40%, respectively, during coadministration of ketoconazole and paroxetine. As coadministered with erythromycin, another CYP3A4 inhibitor, the galantamine AUC increased only 10%. Population PK analysis with a database of 852 patients with Alzheimer's disease showed that the clearance of galantamine was decreased about 25-33% by concurrent administration of amitriptyline (n = 17), fluoxetine (n = 48), fluvoxamine (n = 14), and quinidine (n = 7), known inhibitors of CYP2D6.

Concurrent administration of H2-antagonists demonstrated that ranitidine did not affect the pharmacokinetics of galantamine, and cimetidine increased the galantamine AUC by approximately 16%.

A multiple dose pharmacokinetic study with concurrent administration of memantine, an Nmethyl-D-aspartate (NMDA) receptor antagonist, demonstrated that co-administration of memantine in a dose of 10 mg BID did not affect the pharmacokinetic profile of galantamine (16 mg daily) at steady state.

Effect of RAZADYNE® on the Metabolism of Other Drugs

In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 and CYP2E1. This indicated that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. Multiple doses of galantamine (24 mg/day) had no effect on the pharmacokinetics of digoxin and warfarin (R- and S- forms). Galantamine had no effect on the increased prothrombin time induced by warfarin.

Clinical Trials

The effectiveness of RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide) 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 NINCDSADRDA 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 RAZADYNE® 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 RAZADYNE® 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 RAZADYNE® 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 RAZADYNE® trials was approximately 4.5 units per year.

The ability of RAZADYNE® 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 RAZADYNE® per day, or to placebo, each given in 2 divided doses. Treatment was initiated at 8 mg/day for all patients randomized to RAZADYNE® , 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 RAZADYNE® ).

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 RAZADYNE® -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 - 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 RAZADYNE® 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.

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

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%.

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 RAZADYNE® -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 RAZADYNE® (galantamine hydrobromide) 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 RAZADYNE® -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 RAZADYNE® and placebo have a wide range of responses, but that the RAZADYNE® 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.

Figure 5: Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment With Specified Changes From Baseline in ADAS-cog Scores.

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

The Percentages of Randomized Patients Who Completed the Study Were: Placebo 81%, 24 mg/day 68%, and 32 mg/day 58%.

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%

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 RAZADYNE® -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 RAZADYNE® , 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 RAZADYNE® (galantamine hydrobromide) 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 RAZADYNE® -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 RAZADYNE® and placebo have a wide range of responses, but that the RAZADYNE® 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.

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

The Percentages of Randomized Patients Who Completed the Study Were: Placebo 87%, 24 mg/day 80%, and 32 mg/day 75%

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 RAZADYNE® -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 RAZADYNE® , respectively. The mean ratings for the RAZADYNE® 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 RAZADYNE® 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. RAZADYNE® 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 RAZADYNE® and placebo have a wide range of responses, but that the RAZADYNE® 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.

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

The Percentages of Randomized Patients Who Completed the Study Were: Placebo 90%, 24-32 mg/day 67%

  Change in ADAS-cog
Treatment -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 RAZADYNE® -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 RAZADYNE® ER 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:

RAZADYNE® ER in a flexible dose of 16 to 24 mg once daily; RAZADYNE® 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 RAZADYNE® ER over placebo was seen for the ADAS-cog, but not for the CIBIC-plus. RAZADYNE® ER 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 RAZADYNE® ER Capsules and RAZADYNE® Tablets on the ADAS-cog, CIBIC-plus, and ADCS-ADL were similar in this study.

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Information for Patients and Caregivers

Caregivers should be instructed about the recommended dosage and administration of RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide). RAZADYNE® ER Extended- Release Capsules should be administered once daily in the morning, preferably with food (although not required). 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.

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.

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

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.

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Information for Patients and Caregivers

Caregivers should be instructed about the recommended dosage and administration of RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide). RAZADYNE® ER Extended- Release Capsules should be administered once daily in the morning, preferably with food (although not required). 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.

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.

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

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.

Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Razadyne ER Consumer

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.

Disclaimer

Razadyne ER Consumer (continued)

SIDE EFFECTS: Nausea, vomiting, diarrhea, dizziness, loss of appetite, and weight loss may occur. If any of these effects persist or worsen, notify 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 immediately if any of these unlikely but serious side effects occur: fainting, unusually slow heartbeat, difficult urination.

Tell your doctor immediately if any of these rare but very serious side effects occur: 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 »

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. 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.

Disclaimer

Razadyne ER Consumer (continued)

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 your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. 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.

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.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised October 2010. Copyright(c) 2010 First Databank, Inc.

Razadyne ER Patient Information Including Side Effects

Brand Names: Razadyne, Razadyne ER

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

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 other than those listed in this medication guide.

Razadyne 12 mg

round, brown, imprinted with G 12, JANSSEN

Razadyne 4 mg

round, white, imprinted with G 4, JANSSEN

Razadyne 8 mg

round, pink, imprinted with G 8, JANSSEN

Razadyne ER 16 mg

pink, imprinted with GAL 16

Razadyne ER 24 mg

brown, imprinted with GAL 24

Razadyne ER 8 mg

white, imprinted with GAL 8

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 any of these serious side effects:

  • chest pain, slow heart rate;
  • black, bloody, or tarry stools;
  • coughing up blood or vomit that looks like coffee grounds;
  • weakness, confusion, decreased sweating, extreme thirst, hot dry skin; or
  • urinating less than usual or not at all.

Less serious side effects may include:

  • feeling tired, dizzy, or light-headed;
  • nausea, vomiting, gas, loss of appetite;
  • weight loss; or
  • headache.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. 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 »

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

Before taking galantamine, tell your doctor if you are allergic to any drugs, or 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 medicines that can interact with galantamine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

If you need to have any type of surgery, tell the surgeon ahead of time that you are taking 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.

Galantamine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Side Effects Centers

Razadyne ER Patient Information including How Should I Take

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

Do not use this medication if you are allergic to galantamine.

Before taking galantamine, tell your doctor if you are allergic to any drugs, or if you have:

  • 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 obstructive pulmonary disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take galantamine.

FDA pregnancy category B. This medication is not expected to be harmful to 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 this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

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

Galantamine is usually taken once or twice a day with a meal. You may also take the medication without food. Follow your doctor's instructions.

Do not crush, chew, break, or open an extended-release capsule. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time.

Take the capsule or tablet with a full glass of water. Drink 6 to 8 full glasses of water each day to keep from getting dehydrated while taking galantamine.

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.

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.

If you need to have any type of surgery, tell the surgeon ahead of time that you are taking 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 galantamine at room temperature away from moisture and heat. Do not allow the liquid medicine to freeze.

Side Effects Centers

Razadyne ER Patient Information including If I Miss a Dose

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

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Razadyne ER)?

Seek emergency medical attention if you think you have used too much of this medicine.

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)?

Galantamine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

What other drugs will affect galantamine (Razadyne ER)?

Before taking galantamine, tell your doctor if you are using any of the following drugs:

  • atropine (Donnatal, and others);
  • belladonna;
  • clidinium (Quarzan);
  • dicyclomine (Bentyl);
  • glycopyrrolate (Robinul);
  • hyoscyamine (Anaspaz, Cystospaz, Levsin, and others);
  • ketoconazole (Nizoral);
  • mepenzolate (Cantil);
  • methantheline (Provocholine);
  • methscopolamine (Pamine);
  • paroxetine (Paxil, Pexeva);
  • propantheline (Pro-Banthine); or
  • scopolamine (Transderm-Scop).

This list is not complete and there may be other drugs that can interact with galantamine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

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.

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