2.1. Mild to Moderate Alzheimer's Disease

The dosages of ARICEPT shown to be effective in controlled clinical trials are 5mg and 10mg administered once per day.

The higher dose of 10mg did not provide a statistically significantly greater clinical benefit than 5mg. 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 10mg of ARICEPT might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10mg is a matter of prescriber and patient preference.

2.2. Moderate to Severe Alzheimer's Disease

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

2.3. Titration

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

5.1. Anesthesia

ARICEPT, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

5.2. Cardiovascular Conditions

Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of ARICEPT.

5.3. Nausea and Vomiting

ARICEPT, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10mg/day dose than with the 5mg/day dose, and more frequently with the 23mg dose than with the 10mg dose. Specifically, in a controlled trial that compared a dose of 23mg/day to 10mg/day in patients who had been treated with donepezil 10mg/day for at least three months, the incidence of nausea in the 23mg group was markedly greater than in the patients who continued on 10mg/day (11.8%vs. 3.4%, respectively), and the incidence of vomiting in the 23mg group was markedly greater than in the 10mg group (9.2%vs. 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23mg group was markedly higher than in the 10mg group (2.9%vs. 0.4%, respectively).

Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT, patients should be observed closely at the initiation of treatment and after dose increases.

5.4. Peptic Ulcer Disease and GI Bleeding

Through their primary action, cholinesterase inhibitors 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 at increased risk for developing ulcers, e.g.,those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of ARICEPT in a dose of 5mg/day to 10mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study with 23mg/day showed an increase, relative to 10mg/day, in the incidence of peptic ulcer disease (0.4%vs. 0.2%) and gastrointestinal bleeding from any site (1.1%vs. 0.6%)

5.5. Weight Loss

Weight loss was reported as an adverse event in 4.7% of patients assigned to ARICEPT in a dose of 23mg/day compared to 2.5% of patients assigned to 10mg/day. Compared to their baseline weights, 8.4% of patients taking 23mg/day were found to have a weight decrease of ≥7% by the end of the study, while 4.9% of patients taking 10mg/day were found to have weight loss of ≥7% at the end of the study.

5.6. Genitourinary Conditions

Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction.

5.7. Neurological Conditions: Seizures

Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease.

5.8. Pulmonary Conditions

Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

6.1. Clinical Studies Experience

ARICEPT 5mg/day and 10mg/day

Mild to Moderate Alzheimer's Disease

Adverse Events Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse events for the ARICEPT 5mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5mg/day to 10mg/day was higher at 13%.

The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table1.

Table 1. Most Frequent Adverse Events Leading to Discontinuation from Controlled Clinical Trials by Dose Group
Dose Group	Placebo	5mg/day ARICEPT	10 mg/day ARICEPT
Patients Randomized	355	350	315
Event/%Discontinuing
Nausea	1%	1%	3%
Diarrhea	0%	<1%	3%
Vomiting	<1%	<1%	2%

Most Frequent Adverse Events Seen in Association with the Use of ARICEPT

The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10mg/day and twice the placebo rate, are largely predicted by ARICEPT's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification.

There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5mg/day.

See Table2 for a comparison of the most common adverse events following one and six week titration regimens.

Table 2. Comparison of Rates of Adverse Events in Mild to Moderate Patients Titrated to 10mg/day over 1 and 6Weeks
	No titration		One week titration	Six week titration
Adverse Event	Placebo (n=315)	5mg/day (n=311)	10mg/day (n=315)	10mg/day (n=269)
Nausea	6%	5%	19%	6%
Diarrhea	5%	8%	15%	9%
Insomnia	6%	6%	14%	6%
Fatigue	3%	4%	8%	3%
Vomiting	3%	3%	8%	5%
Muscle cramps	2%	6%	8%	3%
Anorexia	2%	3%	7%	3%

Adverse Events Reported in Controlled Trials

The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age.

Table 3. Adverse Events Reported in Controlled Clinical Trials in Mild to Moderate Alzheimer's Disease in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo Treated Patients
Body System/Adverse Event	Placebo (n=355)	ARICEPT (n=747)
Percent of Patients with any Adverse Event	72	74
Body as a Whole
Headache	9	10
Pain, various locations	8	9
Accident	6	7
Fatigue	3	5
Cardiovascular System
Syncope	1	2
Digestive System
Nausea	6	11
Diarrhea	5	10
Vomiting	3	5
Anorexia	2	4
Hemic and Lymphatic System
Ecchymosis	3	4
Metabolic and Nutritional Systems
Weight Decrease	1	3
Musculoskeletal System
Muscle Cramps	2	6
Arthritis	1	2
Nervous System
Insomnia	6	9
Dizziness	6	8
Depression	<1	3
Abnormal Dreams	0	3
Somnolence	<1	2
Urogenital System
Frequent Urination	1	2

Other Adverse Events Observed During Clinical Trials

ARICEPT has been administered to over 1700individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3months and more than 1000patients have been treated for at least 6months. Controlled and uncontrolled trials in the United States included approximately 900patients. In regards to the highest dose of 10mg/day, this population includes 650patients treated for 3months, 475patients treated for 6months and 116patients treated for over 1year. The range of patient exposure is from 1 to 1214days.

Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900patients from these trials who experienced that event while receiving ARICEPT. All adverse events occurring at least twice are included, except for those already listed in Tables2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100patients; Infrequent adverse events - those occurring in 1/100 to 1/1000patients. These adverse events are not necessarily related to ARICEPT treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.

Body as a Whole:Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness.

Cardiovascular System:Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis.

Digestive System:Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer.

Endocrine System:Infrequent: diabetes mellitus, goiter.

Hemic and Lymphatic System:Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.

Metabolic and Nutritional Disorders:Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.

Musculoskeletal System:Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation.

Nervous System:Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.

Respiratory System:Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.

Skin and Appendages:Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.

Special Senses:Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes.

Urogenital System:Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.

Severe Alzheimer's Disease

Adverse Events Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse events for the ARICEPT patients were approximately 12% compared to 7% for placebo patients. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of ARICEPT patients and at twice or more the incidence seen in placebo, were anorexia (2%vs. 1% placebo), nausea (2%vs. <1% placebo), diarrhea (2%vs. 0% placebo) and urinary tract infection (2%vs. 1% placebo).

Most Frequent Adverse Events Seen in Association with the Use of ARICEPT

The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT and at twice or more the placebo rate, are largely predicted by ARICEPT's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification.

Adverse Events Reported in Controlled Trials

Table4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo.

Table 4. Adverse Events Reported in Controlled Clinical Trials in Severe Alzheimer's Disease in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo Treated Patients
Body System/Adverse Event	Placebo (n=392)	ARICEPT (n=501)
Percent of Patients with any Adverse Event	73	81
Body as a Whole
Accident	12	13
Infection	9	11
Headache	3	4
Pain	2	3
Back Pain	2	3
Fever	1	2
Chest Pain	<1	2
Cardiovascular System
Hypertension	2	3
Hemorrhage	1	2
Syncope	1	2
Digestive System
Diarrhea	4	10
Vomiting	4	8
Anorexia	4	8
Nausea	2	6
Hemic and Lymphatic System
Ecchymosis	2	5
Metabolic and Nutritional Systems
Creatine Phosphokinase Increased	1	3
Dehydration	1	2
Hyperlipemia	<1	2
Nervous System
Insomnia	4	5
Hostility	2	3
Nervousness	2	3
Hallucinations	1	3
Somnolence	1	2
Dizziness	1	2
Depression	1	2
Confusion	1	2
Emotional Lability	1	2
Personality Disorder	1	2
Skin And Appendages
Eczema	2	3
Urogenital System
Urinary Incontinence	1	2

Other Adverse Events Observed During Clinical Trials

ARICEPT has been administered to over 600patients with severe Alzheimer's disease during clinical trials of at least 6months duration, including three double-blind placebo-controlled trials, two of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100patients; Infrequent adverse events - those occurring in 1/100 to 1/1000patients. These adverse events are not necessarily related to ARICEPT treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies.

Body as a Whole:Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia.

Cardiovascular System:Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly.

Digestive System:Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage.

Endocrine System:Infrequent: diabetes mellitus.

Hemic and Lymphatic System:Frequent: anemia; Infrequent: leukocytosis.

Metabolic and Nutritional Disorders:Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent: hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased.

Musculoskeletal System:Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia.

Nervous System:Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia.

Respiratory System:Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma.

Skin and Appendages:Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash.

Special Senses:Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder.

Urogenital System:Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria.

ARICEPT 23mg/day

Moderate to Severe Alzheimer's Disease

ARICEPT 23mg/day has been administered to over 1300individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950patients have been treated for at least six months. The range of patient exposure was from 1 to over 500days.

Adverse Events Leading to Discontinuation

The rate of discontinuation from a controlled clinical trial of ARICEPT 23mg/day due to adverse events was higher (18.6%) than for the 10mg/day treatment group (7.9%). The most common adverse events leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10mg/day are shown in Table5.

Table 5. Most Frequent Adverse Events Leading to Discontinuation from a Controlled Clinical Trial by Treatment Group
Dose Group
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