donepezil hydrochloride

PATIENT PACKAGE INSERT Donepezil Hydrochloride Tablets USP (doe nep' e zil hye'' droe klor' ide) Tablets: 5 mg and 10 mg Donepezil Hydrochloride Orally Disintegrating Tablets USP (doe nep' e zil hye'' droe klor' ide oh-dee-tee) ODT Tablets: 5 mg and 10 mg Read this Patient Information that comes with donepezil hydrochloride tablets and donepezil hydrochloride ODT before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about Alzheimer's disease or treatment for it. If you have questions, ask the doctor or pharmacist. What is donepezil hydrochloride? Donepezil hydrochloride comes as donepezil hydrochloride film-coated tablets in dosage strengths of 5 mg and 10 mg, and as donepezil hydrochloride orally disintegrating tablets (ODT; 5 mg and 10 mg). Except where indicated, all the information about donepezil hydrochloride tablets in this leaflet also applies to donepezil hydrochloride ODT. Donepezil hydrochloride is a prescription medicine to treat mild, moderate, and severe Alzheimer's disease. Donepezil hydrochloride can help with mental function and with doing daily tasks. Donepezil hydrochloride does not work the same in all people. Some people may: Seem much better Get better in small ways or stay the same Get worse over time but slower than expected Not change and then get worse as expected Donepezil hydrochloride does not cure Alzheimer's disease. All patients with Alzheimer's disease get worse over time, even if they take donepezil hydrochloride. Donepezil hydrochloride has not been approved as a treatment for any medical condition in children. Who should not take donepezil hydrochloride? Do not take donepezil hydrochloride if you are allergic to any of the ingredients in donepezil hydrochloride tablets and donepezil hydrochloride ODT or to medicines that contain piperidines. Ask your doctor if you are not sure. See the end of this leaflet for a list of ingredients in donepezil hydrochloride tablets and donepezil hydrochloride ODT. What should I tell my doctor before taking donepezil hydrochloride? Tell the doctor about all of your present or past health problems and conditions. Include: Any heart problems including problems with irregular, slow, or fast heartbeats Asthma or lung problems A seizure Stomach ulcers Difficulty passing urine Liver or kidney problems Trouble swallowing tablets Present pregnancy or plans to become pregnant. It is not known if donepezil hydrochloride can harm an unborn baby. Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Talk to your doctor about the best way to feed your baby if you take donepezil hydrochloride. Tell the doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Donepezil hydrochloride and other medicines may affect each other. Be particularly sure to tell the doctor if you take aspirin or medicines called nonsteroidal anti-inflammatory drugs (NSAIDs). There are many NSAID medicines, both prescription and non-prescription. Ask the doctor or pharmacist if you are not sure if any of your medicines are NSAIDs. Taking NSAIDs and donepezil hydrochloride together may make you more likely to get stomach ulcers. Donepezil hydrochloride taken with certain medicines used for anesthesia may cause side effects. Tell the responsible doctor or dentist that you take donepezil hydrochloride before you have: surgery medical procedures dental surgery or procedures. Know the medicines that you take. Keep a list of all your medicines. Show it to your doctor or pharmacist before you start a new medicine. How should you take donepezil hydrochloride? Take donepezil hydrochloride exactly as prescribed by the doctor. Do not stop donepezil hydrochloride or change the dose yourself. Talk with your doctor first. Take donepezil hydrochloride one time each day. Donepezil hydrochloride can be taken with or without food. Donepezil hydrochloride ODT melts on the tongue. You should drink some water after the tablet melts. If you miss a dose of donepezil hydrochloride, just wait. Take only the next dose at the usual time. Do not take 2 doses at the same time. If donepezil hydrochloride is missed for 7 days or more, talk with your doctor before starting again. If you take too much donepezil hydrochloride at one time, call your doctor or poison control center, or go to the emergency room right away. What are the possible side effects of donepezil hydrochloride? Donepezil hydrochloride may cause the following serious side effects: slow heartbeat and fainting. This happens more often in people with heart problems. Call your doctor right away if you feel faint or lightheaded while taking donepezil hydrochloride. more stomach acid. This raises the chance of ulcers and bleeding, especially when taking donepezil hydrochloride 23 mg. The risk is higher for people who have had ulcers, or take aspirin or other NSAIDs. worsening of lung problems in people with asthma or other lung disease. seizures. difficulty passing urine. Call your doctor right away if you have: fainting. heartburn or stomach pain that is new or won't go away. nausea or vomiting, blood in the vomit, dark vomit that looks like coffee grounds. bowel movements or stools that look like black tar. new or worse asthma or breathing problems. seizures. difficulty passing urine. The most common side effects of donepezil hydrochloride are: nausea diarrhea not sleeping well vomiting muscle cramps feeling tired not wanting to eat These side effects may get better after you take donepezil hydrochloride for a while. This is not a complete list of side effects with donepezil hydrochloride. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should donepezil hydrochloride be stored? Store donepezil hydrochloride tablets and donepezil hydrochloride ODT at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature]. Keep donepezil hydrochloride tablets and all medicines out of the reach of children. General information about donepezil hydrochloride Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information Leaflet. Do not use donepezil hydrochloride for a condition for which it was not prescribed. Do not give donepezil hydrochloride to other people, even if they have the same symptoms or condition. It may harm them. This leaflet summarizes the most important information about donepezil hydrochloride. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride that is written for health professionals. For more information call Unichem Pharmaceuticals (USA), Inc., 1-866-562-4616. What are the ingredients in Donepezil Hydrochloride Tablets and Donepezil Hydrochloride ODT? Active ingredient: donepezil hydrochloride USP Inactive ingredients: Donepezil hydrochloride 5 mg and 10 mg film-coated tablets: Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate. The film coating contains talc, polyethylene glycol, polyvinyl alcohol and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide as a coloring agent. Donepezil hydrochloride ODT 5 mg and 10 mg tablets: Mannitol, silicified microcrystalline cellulose, low substituted hydroxypropyl cellulose, sucralose, orange flavor, sodium stearyl fumarate. The 10 mg tablet contains iron oxide yellow as a coloring agent. Additional patient information leaflets can be obtained by calling Unichem at 1-866-562-4616. Manufactured by: UNICHEM LABORATORIES LTD. Pilerne Ind. Estate, Pilerne, Bardez, Goa 403511, India Manufactured for: East Brunswick, NJ 08816 13014404 06-R-01/2023 Rx Only Unichem Logo

5 WARNINGS AND PRECAUTIONS Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia ( 5.1 ) Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and trioventricular nodes manifesting as bradycardia or heart block ( 5.2 ) Donepezil hydrochloride can cause vomiting. Patients should be observed closely at initiation of treatment and after dose increases ( 5.3 ) Patients should be monitored closely for symptoms of active or occult gastrointestinal (GI) bleeding, especially those at increased risk for developing ulcers ( 5.4 ) The use of donepezil hydrochloride in a dose of 23 mg once daily is associated with weight loss ( 5.5 ) Cholinomimetics may cause bladder outflow obstructions ( 5.6 ) Cholinomimetics are believed to have some potential to cause generalized convulsions ( 5.7 ) Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease ( 5.8 ) 5.1 Anesthesia Donepezil hydrochloride, 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 donepezil hydrochloride. 5.3 Nausea and Vomiting Donepezil hydrochloride, 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 10 mg/day dose than with the 5 mg/day dose, and more frequently with the 23 mg dose than with the 10 mg dose. Specifically, in a controlled trial that compared a dose of 23 mg/day to 10 mg/day in patients who had been treated with donepezil 10 mg/day for at least three months, the incidence of nausea in the 23 mg group was markedly greater than in the patients who continued on 10 mg/day (11.8% vs. 3.4%, respectively), and the incidence of vomiting in the 23 mg group was markedly greater than in the 10 mg group (9.2% vs. 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23 mg group was markedly higher than in the 10 mg group (2.9% vs. 0.4%, respectively). Although in most cases, these effects have been transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil hydrochloride, 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 donepezil hydrochloride in a dose of 5 mg/day to 10 mg/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 23 mg/day showed an increase, relative to 10 mg/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 reaction in 4.7% of patients assigned to donepezil hydrochloride in a dose of 23 mg/day compared to 2.5% of patients assigned to 10 mg/day. Compared to their baseline weights, 8.4% of patients taking 23 mg/day were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of patients taking 10 mg/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 donepezil hydrochloride, 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 ADVERSE REACTIONS Most common adverse reactions in clinical studies of donepezil hydrochloride are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described below and elsewhere in the labeling: Cardiovascular Conditions [see Warnings and Precautions ( 5.2 )] Nausea and Vomiting [see Warnings and Precautions ( 5.3 )] Peptic Ulcer Disease and GI Bleeding [see Warnings and Precautions ( 5.4 )] Weight Loss [see Warnings and Precautions ( 5.5 )] Genitourinary Conditions [see Warnings and Precautions ( 5.6 )] Neurological Conditions: Seizures [see Warnings and Precautions ( 5.7 )] Pulmonary Conditions [see Warnings and Precautions ( 5.8 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Mild to Moderate Alzheimer's Disease Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride 5 mg/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 5 mg/day to 10 mg/day was higher at 13%. The most common adverse reactions 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 Table 1. Table 1 . Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % 5 mg / day Donepezil hydrochloride ( n = 350 ) % 10 mg / day Donepezil hydrochloride ( n = 315 ) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15-and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens. Table 2. Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Reaction Placebo (n=315) % 5 mg/day (n=311) % 10 mg/day (n=315) % 10 mg/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 Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age. Table 3 . Adverse Reactions in Pooled Placebo - Controlled Clinical Trials in Mild toModerate Alzheimer’s Disease Adverse Reaction Placebo ( n = 355 ) % Donepezil hydrochloride ( n = 747 ) % Percent of Patients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer's Disease (Donepezil hydrochloride 5 mg/day and 10 mg/day) Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer's disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension. Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride 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 Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4. Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer's Disease Body Systems/Adverse Reaction Placebo (n=392) % Donepezil hydrochloride (n=501) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 4 10 Anorexia 4 8 Vomiting 4 8 Nausea 4 8 Insomnia 2 6 Ecchymosis 4 5 Headache 2 5 Hypertension 3 4 Pain 2 3 Back Pain 2 3 Eczema 2 3 Hallucinations 2 3 Hostility 1 3 Increase in Creatine Phosphokinase 2 3 Nervousness 1 3 Fever 2 3 Chest Pain 1 2 Confusion <1 2 Dehydration 1 2 Depression 1 2 Dizziness 1 2 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia 1 2 Personality Disorder <1 2 Somnolence 1 2 Syncope 1 2 Urinary Incontinence 1 2 Moderate to Severe Alzheimer's Disease (Donepezil hydrochloride 23 mg/day) Donepezil hydrochloride 23 mg/day has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days. Adverse Reactions Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of donepezil hydrochloride 23 mg/day due to adverse reactions was higher (19%) than for the 10 mg/day treatment group (8%). The most common adverse reactions leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10 mg/day are shown in Table 5. Table 5 . Most Common Adverse Reactions Leading to Discontinuation in Patients with Moderate to Severe Alzeimer's Disease Adverse Reaction 23 mg / day Donepezil hydrochloride ( n = 963 ) % 10 mg / day Donepezil Hydrochloride ( n = 471 ) % Vomiting 3 0 Diarrhea 2 0 Nausea 2 0 Dizziness 1 0 The majority of discontinuations due to adverse reactions in the 23 mg group occurred during the first month of treatment. Most Common Adverse Reactions with donepezil hydrochloride 23 mg/day The most common adverse reactions, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day of donepezil hydrochloride and at a higher frequency than those receiving 10 mg/day of donepezil hydrochloride in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse reactions in patients taking donepezil hydrochloride with or without memantine. Table 6. Adverse Reactions in a Controlled Clinical Trial in Moderate to Severe Alzheimer's Disease Adverse Reaction 23 mg/day Donepezil hydrochloride (n=963) % 10 mg/day Donepezil hydrochloride (n=471) % Percent of Patients with any Adverse Reaction 74 64 Nausea 12 3 Vomiting 9 3 Diarrhea 8 5 Anorexia 5 2 Dizziness 5 3 Weight Loss 5 3 Headache 4 3 Insomnia 3 2 Urinary Incontinence 3 1 Asthenia 2 1 Contusion 2 0 Fatigue 2 1 Somnolence 2 1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of donepezil hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes.

<table ID="ID519" width="101%"><col width="27%"/><col width="20%"/><col width="27%"/><col width="27%"/><tbody><tr><td align="center" valign="top" colspan="4" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Table </content><content styleCode="bold">1</content><content styleCode="bold">. </content><content styleCode="bold">Most </content><content styleCode="bold">Common </content><content styleCode="bold">Adverse </content><content styleCode="bold">Reactions </content><content styleCode="bold">Leading </content><content styleCode="bold">to </content><content styleCode="bold">Discontinuation </content><content styleCode="bold">in </content><content styleCode="bold">Patients </content><content styleCode="bold">with </content><content styleCode="bold">Mild </content><content styleCode="bold">to </content><content styleCode="bold">Moderate </content><content styleCode="bold">Alzheimer&#x2019;s </content><content styleCode="bold">Disease</content> </td></tr><tr><td align="center" valign="middle" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Adverse </content><content styleCode="bold">Reaction</content> </td><td align="center" valign="middle" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Placebo</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">355</content><content styleCode="bold">)</content><content styleCode="bold"> </content><content styleCode="bold">%</content> </td><td align="center" valign="middle" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">5 </content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">day </content><content styleCode="bold">Donepezil </content><content styleCode="bold">hydrochloride</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">350</content><content styleCode="bold">)</content><content styleCode="bold"> </content><content styleCode="bold">%</content> </td><td align="center" valign="middle" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">10 </content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">day </content><content styleCode="bold">Donepezil </content><content styleCode="bold">hydrochloride</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">315</content><content styleCode="bold">)</content><content styleCode="bold"> </content><content styleCode="bold">%</content> </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Nausea </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Diarrhea </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">0 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">&lt;1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Vomiting </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">&lt;1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">&lt;1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td></tr></tbody></table>

<table ID="ID521" width="472" styleCode="Noautorules"><col width="104"/><col width="85"/><col width="85"/><col width="94"/><col width="104"/><tbody><tr><td colspan="5" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Table 2. Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule"/><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> No titration</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> One week titration</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Six week titration</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Reaction </content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (n=315)</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 5 mg/day</content> <content styleCode="bold"> (n=311)</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 10 mg/day</content> <content styleCode="bold"> (n=315)</content> <content styleCode="bold"> %</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 10 mg/day</content> <content styleCode="bold"> (n=269)</content> <content styleCode="bold"> %</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Insomnia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fatigue </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Muscle cramps </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anorexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr></tbody></table>

<table ID="ID523" width="99%"><col width="43%"/><col width="28%"/><col width="28%"/><tbody><tr><td align="center" valign="top" colspan="3" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Table </content><content styleCode="bold">3</content><content styleCode="bold">. </content><content styleCode="bold">Adverse </content><content styleCode="bold">Reactions </content><content styleCode="bold">in </content><content styleCode="bold">Pooled </content><content styleCode="bold">Placebo</content><content styleCode="bold">-</content><content styleCode="bold">Controlled </content><content styleCode="bold">Clinical </content><content styleCode="bold">Trials </content><content styleCode="bold">in </content><content styleCode="bold">Mild </content><content styleCode="bold">toModerate </content><content styleCode="bold">Alzheimer&#x2019;s </content><content styleCode="bold">Disease</content> </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Adverse </content><content styleCode="bold">Reaction </content> </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Placebo</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">355</content><content styleCode="bold">)</content><content styleCode="bold"> </content><content styleCode="bold">%</content> </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Donepezil </content><content styleCode="bold">hydrochloride </content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">747</content><content styleCode="bold">)</content><content styleCode="bold"> </content><content styleCode="bold">%</content> </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">Percent </content><content styleCode="bold">of </content><content styleCode="bold">Patients </content><content styleCode="bold">with </content><content styleCode="bold">any </content><content styleCode="bold">Adverse </content><content styleCode="bold">Reaction </content> </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">72</content> </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule"><content styleCode="bold">74</content> </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Nausea </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">6 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">11 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Diarrhea </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">5 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">10 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Headache </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">9 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">10 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Insomnia </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">6 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">9 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Pain, various locations </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">8 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">9 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Dizziness </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">6 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">8 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Accident </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">6 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">7 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Muscle Cramps </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">6 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Fatigue </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">5 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Vomiting </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">5 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Anorexia </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">4 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Ecchymosis </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">4 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Abnormal Dreams </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">0 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Depression </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">&lt;1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Weight Loss </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">3 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Arthritis </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Frequent Urination </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Somnolence </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">&lt;1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td></tr><tr><td align="justify" valign="top" styleCode=" Lrule Rrule Botrule Toprule">Syncope </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">1 </td><td align="center" valign="top" styleCode=" Lrule Rrule Botrule Toprule">2 </td></tr></tbody></table>