DONEPEZIL HYDROCHLORIDE: Package Insert and Label Information (Page 3 of 4)

14.2 Moderate to Severe Alzheimers Disease

The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to severe Alzheimer’s disease was established in studies employing doses of 10 mg/day and 23 mg/day. Results of a controlled clinical trial in moderate to severe Alzheimer’s Disease that compared donepezil hydrochloride 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of donepezil hydrochloride provided additional benefit.

Swedish 6 Month Study (10 mg/day)

The effectiveness of donepezil hydrochloride as a treatment for severe Alzheimer’s disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (6 month study) in patients with probable or possible Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1 to 10. Two hundred and forty eight (248) patients with severe Alzheimer’s disease were randomized to donepezil hydrochloride or placebo. For patients randomized to donepezil hydrochloride, treatment was initiated at 5 mg once daily for 28 days and then increased to 10 mg once daily. At the end of the 6 month treatment period, 90.5% of the donepezil hydrochloride treated patients were receiving the 10 mg/day dose. The mean age of patients was 84.9 years, with a range of 59 to 99. Approximately 77% of patients were women, and 23% were men. Almost all patients were Caucasian. Probable Alzheimer’s disease was diagnosed in the majority of the patients (83.6% of donepezil hydrochloride treated patients and 84.2% of placebo treated patients).

Study Outcome Measures:

The effectiveness of treatment with donepezil hydrochloride was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on donepezil hydrochloride experienced significant improvement on both measures compared to placebo.

The ability of donepezil hydrochloride to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.

Daily function was assessed using the Modified Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL-severe). The ADCS-ADL-severe is derived from the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment. The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient.

Effects on the SIB

Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 6 months of the study. At 6 months of treatment, the mean difference in the SIB change scores for donepezil hydrochloride treated patients compared to patients on placebo was 5.9 points. Donepezil hydrochloride treatment was statistically significantly superior to placebo.

Figure 7. Time Course of the Change from Baseline in SIB Score for Patients Completing 6 Months of Treatment.

Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to donepezil hydrochloride and to placebo have a wide range of responses, the curves show that the donepezil hydrochloride group is more likely to show a greater improvement in cognitive performance.

Figure 8. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with Particular Changes from Baseline in SIB Scores.

Figure 9. Time Course of the Change from Baseline in ADCS-ADL-Severe Score for Patients Completing 6 Months of Treatment.

Effects on the ADCS-ADL-severe

Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 6 months of the study. After 6 months of treatment, the mean difference in the ADCS-ADL-severe change scores for donepezil hydrochloride treated patients compared to patients on placebo was 1.8 points. Donepezil hydrochloride treatment was statistically significantly superior to placebo.

Figure 10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores. While both patients assigned to donepezil hydrochloride and placebo have a wide range of responses, the curves demonstrate that the donepezil hydrochloride group is more likely to show a smaller decline or an improvement.

Figure 10. Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with Particular Changes from Baseline in ADCS-ADL-Severe Scores.

Japanese 24-Week Study (10 mg/day)

In a study of 24 weeks duration conducted in Japan, 325 patients with severe Alzheimer’s disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over a maximum of 6 weeks. Two hundred and forty eight (248) patients completed the study, with similar proportions of patients completing the study in each treatment group. The primary efficacy measures for this study were the SIB and CIBIC-plus.

At 24 weeks of treatment, statistically significant treatment differences were observed between the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC-plus. The 5 mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC-plus.

Study of 23 mg/day

The effectiveness of donepezil hydrochloride 23 mg/day as a treatment for moderate to severe Alzheimer’s disease has been demonstrated by the results of a randomized, double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer’s disease. The controlled clinical study was conducted globally in patients with probable Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0 to 20. Patients were required to have been on a stable dose of donepezil hydrochloride 10 mg/day for at least 3 months prior to screening. One thousand four hundred and thirty four (1434) patients with moderate to severe Alzheimer’s disease were randomized to 23 mg/day or 10 mg/day. The mean age of patients was 73.8 years, with a range of 47 to 90. Approximately 63% of patients were women, and 37% were men. Approximately 36% of the patients were taking memantine throughout the study.

Study Outcome Measures:

The effectiveness of treatment with 23 mg/day was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment.

The ability of 23 mg/day to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.

The ability of 23 mg/day to produce an overall clinical effect was assessed using a Clinician’s Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines four major areas of patient function: General, Cognitive, Behavioral, and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations 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 “markedly worse.”

Effects on the SIB

Figure 11 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the LS mean difference in the SIB change scores for 23 mg/day-treated patients compared to patients treated with 10 mg was 2.2 units (p = 0.0001). The dose of 23 mg/day was statistically significantly superior to the dose of 10 mg/day.

Figure 11. Time-course of the Change from Baseline in SIB Score for Patients Completing 24 Weeks of Treatment.

Figure 12 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to 23 mg/day and to 10 mg/day have a wide range of responses, the curves show that the 23 mg-group is more likely to show a greater improvement in cognitive performance. When such curves are shifted to the left, this indicates a greater percentage of patients responding to treatment on the SIB.

Figure 12. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with Specified Changes from Baseline SIB Scores.

Effects on the CIBIC-plus

Figure 13 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the end of 24 weeks of treatment. The mean difference between the 23 mg/day and 10 mg/day treatment groups was 0.06 units. This difference was not statistically significant.

Figure 13. Frequency Distribution of CIBIC-plus Scores at Week 24.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Donepezil Hydrochloride Tablets

Donepezil Hydrochloride Tablets, 23 mg are reddish brown, round, film coated tablets, containing 23 mg of donepezil hydrochloride, debossed with ‘G52’ on one side and ‘LU’ on the other side, which are supplied as follows:

NDC 68180-527-06 Bottle of 30s

NDC 68180-527-09 Bottle of 90s

Storage: Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Instruct patients and caregivers to take donepezil hydrochloride only once per day, as prescribed.

Instruct patients and caregivers that donepezil hydrochloride can be taken with or without food. Donepezil hydrochloride 23 mg tablets should be swallowed whole without the tablets being split, crushed or chewed.

Advise patients and caregivers that donepezil hydrochloride may cause nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and decreased appetite.

Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States.

Manufactured by:

Lupin Limited

Goa 403 722

INDIA.

Revised: January 18, 2019 ID#: 259016

PATIENT PACKAGE INSERT

Donepezil Hydrochloride Tablets, 23 mg

(doe nep′ e zil hye″ droe klor′ ide)

Rx Only

Read this Patient Information that comes with donepezil hydrochloride tablets 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 are Donepezil Hydrochloride Tablets?

Donepezil hydrochloride comes as donepezil hydrochloride film-coated tablets in dosage strengths of 5 mg, 10 mg and 23 mg.

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 tablets?

Do not take donepezil hydrochloride tablets if you are allergic to any of the ingredients in donepezil hydrochloride tablets 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.

What should I tell my doctor before taking donepezil hydrochloride tablets?

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 tablets?

• Take donepezil hydrochloride tablets exactly as prescribed by the doctor. Do not stop donepezil hydrochloride tablets or change the dose yourself. Talk with your doctor first.
• Take donepezil hydrochloride tablets one time each day. Donepezil hydrochloride tablets can be taken with or without food.
• Donepezil hydrochloride 23 mg tablets should be swallowed whole. Do not split, crush, or chew the tablets.
• If you miss a dose of donepezil hydrochloride tablets, just wait. Take only the next dose at the usual time. Do not take 2 doses at the same time.
• If donepezil hydrochloride tablet is missed for 7 days or more, talk with your doctor before starting again.
• If you take too much donepezil hydrochloride tablets 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 tablets?

Donepezil hydrochloride tablets 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 tablets.
• more stomach acid. This raises the chance of ulcers and bleeding, especially when taking donepezil hydrochloride tablets 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 tablets are:

• anausea
• diarrhea
• not sleeping well
• vomiting
• muscle cramps
• feeling tired
• not wanting to eat

These side effects may get better after you take donepezil hydrochloride tablets for a while. This is not a complete list of side effects with donepezil hydrochloride tablets. 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.You may also report side effect to Lupin Pharmaceuticals Inc. at 1-800-399-2561.

How should donepezil hydrochloride tablets be stored?

Store donepezil hydrochloride tablets at room temperature between 59° to 86°F (15° to 30°C).

Keep donepezil hydrochloride tablets and all medicines out of the reach of children.

General information about donepezil hydrochloride tablets

Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information Leaflet. Do not use donepezil hydrochloride tablets for a condition for which it was not prescribed. Do not give donepezil hydrochloride tablets 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 tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride tablets that is written for health professionals.

For more information, go to www.lupinpharmaceuticals.com or call Lupin Pharmaceuticals, Inc. at 1-800-399-2561

What are the ingredients in donepezil hydrochloride tablets?

Active Ingredient: Donepezil Hydrochloride

Inactive Ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, sodium starch glycolate. The film coating includes hypromellose, iron oxide red, polyethylene glycol, talc and titanium dioxide.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States.

Manufactured by:

Lupin Limited

Goa 403 722

INDIA.

Revised: January 18, 2019 ID#: 259017