Alzheimer’s Disease – Therapeutic agents

Mechanism of Action
Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission.

Donepezil hydrochloride 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 acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.

DOSAGE AND ADMINISTRATION
ARICEPT should be taken in the evening, just prior to retiring.

ARICEPT can be taken with or without food.

The 23 mg tablet should not be split, crushed or chewed because this may increase its rate of absorption.

Allow ARICEPT ODT to dissolve on the tongue and follow with water.

Mild to Moderate Alzheimer's Disease
The dosages of ARICEPT shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.

The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of ARICEPT might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.

Moderate to Severe Alzheimer's Disease
ARICEPT has been shown to be effective in controlled clinical trials at doses of 10 mg and 23 mg administered once daily. Results of a controlled clinical trial in moderate to severe Alzheimer's Disease that compared ARICEPT 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of ARICEPT provided additional benefit.

Titration
The recommended starting dose of ARICEPT is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because ARICEPT steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks. A dose of 23 mg once daily can be administered once patients have been on a dose of 10 mg once daily for at least 3 months.

DOSAGE FORMS AND STRENGTHS
ARICEPT is supplied as film-coated, round tablets containing 5 mg, 10 mg, or 23 mg of donepezil hydrochloride.
The 5 mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.
The 10 mg tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.
The 23 mg tablets are reddish. The strength, in mg (23), is debossed on one side, and ARICEPT is debossed on the other side.
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ARICEPT ODT is supplied as round tablets containing either 5 mg or 10 mg of donepezil hydrochloride.
The 5 mg orally disintegrating tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.
The 10 mg orally disintegrating tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.

DOSAGE AND ADMINISTRATION

Galantamine Hydrobromide Extended-Release Capsules
Galantamine Hydrobromide Extended-Release Capsules should be administered once daily in the morning, preferably with food.

The recommended starting dosage of Galantamine Hydrobromide Extended-Release Capsules 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 Galantamine Hydrobromide Extended-Release Capsules shown to be effective in a controlled clinical trial is 16 to 24 mg/day.

Patients currently being treated with Galantamine Tablets can convert to Galantamine Hydrobromide Extended-Release Capsules by taking their last dose of Galantamine Tablets in the evening and starting Galantamine Hydrobromide Extended-Release Capsules once daily treatment the next morning. Converting from Galantamine Tablets to Galantamine Hydrobromide Extended-Release Capsules should occur at the same total daily dosage.
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Galantamine Immediate-Release Tablets
The dosage of Galantamine Tablets shown to be effective in controlled clinical trials is 16 to 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 to 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 Galantamine Tablets might provide additional benefit for some patients.

The recommended starting dosage of Galantamine Tablets 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.

Galantamine Tablets 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 Galantamine Hydrobromide Extended-Release Capsules and Galantamine Tablets 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 Galantamine Hydrobromide Extended-Release Capsules and Galantamine Tablets are lost, however, when the drug is discontinued.
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Hepatic Impairment
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 to 9), the total daily dosage should generally not exceed 16 mg/day. The use of Galantamine Hydrobromide Extended-Release Capsules and Galantamine Tablets in patients with severe hepatic impairment (Child-Pugh score of 10 to 15) is not recommended.

Renal Impairment
For patients with moderate renal impairment the dosage should generally not exceed 16 mg/day. In patients with severe renal impairment (creatinine clearance < 9 mL/min), the use of Galantamine Hydrobromide Extended-Release Capsules and Galantamine Tablets is not recommended.

[Supplied: 4,8,12mg tabs and 8, 16, 24 mg ER capsules]

Mechanism of Action
Although the precise mechanism of action of rivastigmine is unknown, it is thought 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. Therefore, the effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process.

DOSAGE AND ADMINISTRATION
Recommended Dosing
Exelon should be taken with meals in divided doses in the morning and evening.

Alzheimer’s Disease----------------------------
The dosage of Exelon shown to be effective in controlled clinical trials in Alzheimer’s disease is 6 mg to 12 mg per day, administered twice a day (daily doses of 3 mg to 6 mg twice a day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial.

Initial Dose
Initiate treatment with the 1.5 mg twice a day with Exelon.

Dose Titration
After a minimum of 2 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).

Parkinson’s Disease Dementia----------------------------
The dosage of Exelon shown to be effective in the single controlled clinical trial conducted in dementia associated with Parkinson’s disease is 3 mg to 12 mg per day, administered twice a day (daily doses of 1.5 mg to 6 mg twice a day).

Initial Dose
Initiate treatment with the 1.5 mg twice a day with Exelon.

Dose Titration
After a minimum of 4 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day).

Interruption of Treatment
If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level.

If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower dose of Exelon. If dosing is interrupted for more than 3 days, treatment should be restarted with 1.5 mg twice a day and titrated as described above

Important Administration Instructions
Caregivers should be instructed in the correct procedure for administering Exelon Oral Solution. In addition, they should be directed to the Instruction Sheet (included with the product) describing how the solution is to be administered. Caregivers should direct questions about the administration of the solution to either their physician or pharmacist.

Patients should be instructed to remove the oral dosing syringe provided in its protective case, and using the provided syringe, withdraw the prescribed amount of Exelon Oral Solution from the container. Each dose of Exelon Oral Solution may be swallowed directly from the syringe or first mixed with a small glass of water, cold fruit juice, or soda. Patients should be instructed to stir and drink the mixture.

Exelon Oral Solution and Exelon Capsules may be interchanged at equal doses.

EXELON (rivastigmine) patch, extended release -------------------
Consider dose adjustments in patients with:
-Mild to moderate hepatic impairment
-Low (<50 kg) body weight

Recommended Dosing
Initial Dose
Initiate treatment with one 4.6 mg/24 hours Exelon Patch applied to the skin once daily.

Dose Titration
Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been well tolerated. For mild to moderate AD and PDD patients continue the recommended effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists. Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose. For patients with severe AD, 13.3 mg/24 hours is the recommended effective dose. Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions.

Mild to Moderate Alzheimer’s Disease and Mild to Moderate Parkinson’s Disease Dementia
The effective dosage of Exelon Patch is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Severe Alzheimer’s Disease
The effective dosage of Exelon Patch in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Interruption of Treatment
If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength Exelon Patch. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours Exelon Patch and titrate as described above.

Dosing in Specific Populations
Dosing Modifications in Patients with Hepatic Impairment
Consider using the 4.6 mg/24 hours Exelon Patch as both the initial and maintenance dose in patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment

Dosing Modifications in Patients with Low Body Weight
Because rivastigmine blood levels vary with weight, carefully titrate and monitor patients with low body weight (<50kg) for toxicities (e.g., excessive nausea, vomiting) and consider reducing the maintenance dose to the 4.6 mg/24 hours Exelon Patch if such toxicities develop.

Switching to Exelon Patch from Exelon Capsules or Exelon Oral Solution
Patients treated with Exelon Capsules or Oral Solution may be switched to Exelon Patch as follows:

A patient who is on a total daily dose of <6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours Exelon Patch.
A patient who is on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 hours Exelon Patch.

Instruct patients or caregivers to apply the first patch on the day following the last oral dose.

Important Administration Instructions
Exelon Patch is for transdermal use on intact skin.

(a) Do not use the patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

(b) Apply the Exelon Patch once a day

-Press down firmly for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing.
-Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient. If sites on the back are not accessible, apply the patch to the upper arm or chest.
-Do not apply to a skin area where cream, lotion, or powder has recently been applied.

(c) Do not apply to skin that is red, irritated, or cut.

(d) Replace the Exelon Patch with a new patch every 24 hours. Instruct patients to only wear 1 patch at a time (remove the previous day’s patch before applying a new patch). If a patch falls off or if a dose is missed, apply a new patch immediately and then replace this patch the following day at the usual application time.

(e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days. Do not apply a new patch to the same location for at least 14 days.

(f) May wear the patch during bathing and in hot weather. But avoid long exposure to external heat sources (excessive sunlight, saunas, solariums).

(g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children.

DOSAGE FORMS AND STRENGTHS
Exelon Capsules
Capsules, containing rivastigmine tartrate equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of rivastigmine base, are available as follows:
1.5 mg capsule – yellow, “Exelon 1,5 mg” is printed in red on the body of the capsule.

3 mg capsule – orange, “Exelon 3 mg” is printed in red on the body of the capsule.

4.5 mg capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule.

6 mg capsule – orange and red, “Exelon 6 mg” is printed in red on the body of the capsule.

Exelon Oral Solution
Oral Solution is a clear yellow, solution containing rivastigmine tartrate equivalent to 2 mg/mL of rivastigmine base.

Exelon Patch is available in 3 strengths. Each patch has a beige backing layer labeled as either:

EXELON® PATCH 4.6 mg/24 hours, AMCX
EXELON® PATCH 9.5 mg/24 hours, BHDI
EXELON® PATCH 13.3 mg/24 hours, CNFU

Removed from the U.S. market

Mechanism of Action
Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

INDICATIONS AND USAGE
NAMENDA is an N-methyl-D-aspartate (NMDA) receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

DOSAGE AND ADMINISTRATION
The recommended starting dose of NAMENDA is 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day.

NAMENDA can be taken with or without food. If a patient misses a single dose of NAMENDA, that patient should not double up on the next dose. The next dose should be taken as scheduled.If a patient fails to take NAMENDA for several days, dosing may need to be resumed at lower doses and retitrated as described above.

Do not mix NAMENDA oral solution with any other liquid. The oral solution is administered with a dosing device that comes with the drug and consists of a syringe, syringe adaptor cap, tubing and other supplies a patient needs to administer the drug. The supplied syringe should be used to withdraw the correct volume of oral solution and the oral solution should be slowly squirted into the corner of the patient's mouth.

Special Populations
Renal Impairment
A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 -29 mL/min based on the Cockroft-Gault equation).

Hepatic Impairment
NAMENDA should be administered with caution to patients with severe hepatic impairment

Supplied:
Tablets: 5 mg and 10 mg
Oral Solution: 2 mg/mL

Manju T. Beier, PharmD, FASCP, Elaine R. Peskind, MD, Mark Sey, RPh, CGP, FASC. March 2004. Optimizing Care Management Plans Across the Spectrum of Alzheimer's Disease. Source: (Clinical Geriatrics) https://www.hmpcommunications.com/cg/displayArticle.cfm?articleID=cgsupp1952

"Treatment guidelines from the AAN recommend cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease, where symptomatic benefit is seen in 20-30% of patients, and 70-80% stabilize.41 Vitamin E can be taken as 1000 IU twice a day. Selegiline is second-line therapy because vitamin E was numerically superior in the Sano et al trial,20 and selegiline does have side effects.41 Nonsteroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 inhibitors, and estrogen do not have sufficient supportive data and are not advocated by the AAN at this time for the treatment of already-established dementia.41 Patients with unspecified dementia may benefit from Gingko biloba, but evidence-based efficacy data are insufficient.

In summary, cholinergic agents are considered first-line treatment in patients with mild-to-moderate AD because they have been in use the longest. These drugs initially improve and transiently maintain cognitive abilities. Cognitive abilities worsen over time, indicating that treatment does not stop but may delay the progression of Alzheimer’s disease. Recently-approved memantine is now recommended for the treatment of moderate-to-severe dementia of the Alzheimer’s type as monotherapy or in combination with AChE inhibitors.

The dual-therapy study showed that combination memantine and donepezil demonstrated superior efficacy to treatment with donepezil alone. Severely impaired nursing home patients showed improvement on both functional and global measures, as well as reduced care dependence. "

Drug UPDATES:  NAMZARIC ™ (memantine hydrochloride extended-release and donepezil hydrochloride) capsules, for oral use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action: NAMZARIC capsules contain two approved medications: memantine hydrochloride extended-release and donepezil hydrochloride. Each of those medications is postulated to have a different mechanism in Alzheimer's disease.

Memantine
Persistent activation of central nervous system NMDA receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

Donepezil
Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil prevents or slows neurodegeneration in patients with Alzheimer's disease.

INDICATIONS AND USAGE:
NAMZARIC is a combination of memantine hydrochloride extended-release, a NMDA receptor antagonist, and donepezil hydrochloride, an acetylcholinesterase inhibitor, indicated for the treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on:

memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg, or
memantine hydrochloride (5 mg twice daily or 14 mg extended-release once daily) and donepezil hydrochloride 10 mg.

HOW SUPPLIED:
NAMZARIC capsules:
14 mg memantine hydrochloride extended-release and 10 mg donepezil hydrochloride
28 mg memantine hydrochloride extended-release and 10 mg donepezil hydrochloride