Exelon
Generic Name: rivastigmine
tartrate
Dosage Form: capsules and oral solution
INDICATIONS AND USAGE
Alzheimer’s
Disease
Exelon is indicated for the treatment of mild to
moderate dementia of the Alzheimer's type (AD).
Parkinson’s Disease Dementia
Exelon is indicated for the treatment of mild to
moderate dementia associated with Parkinson’s disease.
2
DOSAGE AND ADMINISTRATION
Dosing in Alzheimer’s Disease
Exelon should be taken with meals in
divided doses in the morning and evening.
The recommended dosage of Exelon Oral
Solution and Capsules 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).
Dosing
in Parkinson’s Disease Dementia
Exelon should be taken with meals in divided doses
in the morning and evening.
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 [see Warnings and
Precautions (5.1)].
Dosing
in Specific Populations
Dosing Modifications in Patients with
Renal Impairment
Patients with moderate and severe renal impairment
may be able to only tolerate lower doses.
Dosing Modifications in Patients with
Hepatic Impairment
Patients with mild (Child-Pugh score 5 to 6) and
moderate (Child-Pugh score 7 to 9) hepatic impairment may be able to only
tolerate lower doses. No data are available on the use of rivastigmine in
patients with severe hepatic impairment.
Dosing Modifications in Patients with
Low Body Weight
Carefully titrate and monitor patients with low
body weight (less than 50 kg) for toxicities (e.g., excessive nausea,
vomiting), and consider reducing the dose if such toxicities develop.
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 [see Patient Counseling Information (17)].
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.
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.
For a full list of excipients, see Description
(11).
4
CONTRAINDICATIONS
Exelon is contraindicated in patients
with:
· known
hypersensitivity to rivastigmine, other carbamate derivatives or other
components of the formulation [see Description (11)].
· a previous history of
application site reaction with rivastigmine transdermal patch suggestive of
allergic contact dermatitis, in the absence of negative allergy testing [see
Warnings and Precautions (5.2)].
Isolated cases of generalized skin reactions have
been described in postmarketing experience [see
Adverse Reactions (6.2)].
5
WARNINGS AND PRECAUTIONS
Gastrointestinal Adverse Reactions
Exelon can cause gastrointestinal
adverse reactions, including significant nausea, vomiting, diarrhea,
anorexia/decreased appetite, and weight loss. Dehydration may result from
prolonged vomiting or diarrhea and can be associated with serious outcomes. The
incidence and severity of these reactions are dose-related [see Adverse
Reactions (6.1)]. For this reason, patients should always be started at a
dose of 1.5 mg twice a day and titrated to their maintenance dose.
If treatment is interrupted for longer than 3 days,
treatment should be reinitiated with the lowest daily dose [see
Dosage and Administration (2.3)] to reduce the possibility of severe vomiting
and its potentially serious sequelae (e.g., there has been one postmarketing
report of severe vomiting with esophageal rupture following inappropriate
reinitiation of treatment with a 4.5-mg dose after 8 weeks of treatment
interruption).
Inform caregivers to monitor for gastrointestinal
adverse reactions and to inform the physician if they occur. It is critical to
inform caregivers that if therapy has been interrupted for more than 3 days
because of intolerance, the next dose should not be administered without
contacting the physician regarding proper retitration.
Allergic Dermatitis
There have been isolated postmarketing reports of
patients experiencing disseminated allergic dermatitis when administered
rivastigmine irrespective of the route of administration (oral or transdermal).
Treatment should be discontinued if disseminated allergic dermatitis
occurs [see Contraindications (4)]. Patients and caregivers
should be instructed accordingly [see
Patient Counseling Information (17)].
In patients who develop application site reactions
suggestive of allergic contact dermatitis to Exelon PATCH and who still require
rivastigmine, treatment should be switched to oral rivastigmine only after
negative allergy testing and under close medical supervision. It is possible
that some patients sensitized to rivastigmine by exposure to rivastigmine patch
may not be able to take rivastigmine in any form.
Other
Adverse Reactions from Increased Cholinergic Activity
Neurologic Effects
Extrapyramidal Symptoms: Cholinomimetics,
including rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening of parkinsonian symptoms, particularly tremor, has been observed in
patients with dementia associated with Parkinson’s disease who were treated
with Exelon Capsules.
Seizures: Drugs that increase cholinergic
activity are believed to have some potential for causing seizures. However,
seizure activity also may be a manifestation of Alzheimer's disease.
Peptic Ulcers/Gastrointestinal
Bleeding
Cholinesterase inhibitors, including rivastigmine,
may be expected to increase gastric acid secretion due to increased cholinergic
activity. Monitor patients using Exelon 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
rivastigmine have shown no significant increase, relative to placebo, in the
incidence of either peptic ulcer disease or gastrointestinal bleeding.
Use with Anesthesia
Rivastigmine, as a cholinesterase inhibitor, is
likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Cardiac Conduction Effects
Because rivastigmine increases cholinergic
activity, use of rivastigmine may have vagotonic effects on heart rate (e.g.,
bradycardia). The potential for this action may be particularly important in
patients with sick sinus syndrome or other supraventricular cardiac conduction
conditions. In clinical trials, rivastigmine was not associated with any
increased incidence of cardiovascular adverse events, heart rate or blood
pressure changes, or electrocardiogram (ECG) abnormalities. Syncopal episodes have
been reported in 3% of patients receiving 6 mg to 12 mg per day of Exelon,
compared to 2% of placebo patients.
Genitourinary Effects
Although not observed in clinical trials of
rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.
Pulmonary Effects
Drugs that increase cholinergic activity, including
rivastigmine, should be used with care in patients with a history of asthma or
obstructive pulmonary disease.
Impairment in Driving or Use of Machinery
Dementia may cause gradual impairment of driving
performance or compromise the ability to use machinery. The administration
of rivastigmine may also result in adverse reactions that are detrimental to
these functions. During treatment with the Exelon, routinely evaluate the
patient’s ability to continue driving or operating machinery.
6
ADVERSE REACTIONS
The following adverse reactions are
described below and elsewhere in the labeling:
Gastrointestinal
Adverse Reactions [see Warnings and Precautions (5.1)]Allergic Dermatitis [see
Warnings and Precautions (5.2)]Other Adverse Reactions from
Increased Cholinergic Activity [see Warnings
and Precautions (5.3)]
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.
Exelon has been administered to over 5,297
individuals during clinical trials worldwide. Of these, 4,326 patients have
been treated for at least 3 months, 3,407 patients have been treated for at
least 6 months, 2,150 patients have been treated for 1 year, 1,250 patients
have been treated for 2 years, and 168 patients have been treated for over 3
years. With regard to exposure to the highest dose, 2,809 patients were exposed
to doses of 10 mg to 12 mg, 2,615 patients treated for 3 months, 2,328 patients
treated for 6 months, 1,378 patients treated for 1 year, 917 patients treated
for 2 years, and 129 patients treated for over 3 years.
Mild to Moderate Alzheimer’s Disease
Most Common Adverse Reactions
The most common adverse reactions, defined as those
occurring at a frequency of at least 5% and twice the placebo rate, are largely
predicted by Exelon's cholinergic effects. These include nausea, vomiting,
anorexia, dyspepsia, and asthenia.
Gastrointestinal Adverse Reactions
Exelon use is associated with significant nausea,
vomiting, and weight loss [see Warnings and Precautions (5.1)].
Discontinuation Rates
The rate of discontinuation due to adverse events
in controlled clinical trials of Exelon (rivastigmine tartrate) was 15% for
patients receiving 6 mg to 12 mg per day compared to 5% for patients on placebo
during forced weekly dose titration. While on a maintenance dose, the rates
were 6% for patients on Exelon compared to 4% for those on placebo.
The most common adverse reactions leading to
discontinuation, defined as those occurring in at least 2% of patients and at
twice the incidence seen in placebo patients, are shown in Table 1.
Table 1: Most Frequent Adverse Reactions Leading to Withdrawal from
Clinical Trials during Titration and Maintenance in Patients Receiving 6 mg
to 12 mg per day Exelon Using a Forced-Dose Titration
|
|
Study Phase
|
Titration
|
Maintenance
|
Overall
|
|
|
Exelon
≥6
to 12 mg/day
|
Placebo
|
Exelon
≥6
to 12 mg/day
|
Placebo
|
Exelon
≥6
to 12 mg/day
|
Placebo
|
|
|
(n=1,189)
|
(n=868)
|
(n=987)
|
(n=788)
|
(n=1,189)
|
(n=868)
|
|
Event/%
Discontinuing
|
|
|
|
|
|
|
|
Nausea
|
8
|
<1
|
1
|
<1
|
8
|
1
|
|
Vomiting
|
4
|
<1
|
1
|
<1
|
5
|
<1
|
|
Anorexia
|
2
|
0
|
1
|
<1
|
3
|
<1
|
|
Dizziness
|
2
|
<1
|
1
|
<1
|
2
|
<1
|
Adverse Reactions Observed at an
Incidence of at Least 2%
Table 2 lists adverse reactions that occurred in at
least 2% of patients in placebo-controlled trials and for which the rate of
occurrence was greater for patients treated with Exelon doses of 6 mg to 12 mg
per day than for those treated with placebo.
In general, adverse reactions were less frequent
later in the course of treatment.
No systematic effect of race or age could be
determined from the incidence of adverse reactions in the controlled studies.
Nausea, vomiting and weight loss were more frequent in women than men.
Table 2: Proportion of Adverse Reactions Observed with a Frequency of ≥2% and at a Rate Greater than Placebo in Clinical
Trials
|
|
Body
System/Adverse Reaction
|
Exelon
(6-12
mg/day)
(n=1,189)
|
Placebo
(n=868)
|
|
Percent of Patients with any Adverse Event
|
92
|
79
|
|
|
|
Autonomic Nervous System
|
|
Increased Sweating
|
4
|
1
|
|
Syncope
|
3
|
2
|
|
Body as a Whole
|
|
Fatigue
|
9
|
5
|
|
Asthenia
|
6
|
2
|
|
Malaise
|
5
|
2
|
|
Decreased Weight**
|
3
|
<1
|
|
Cardiovascular Disorders, General
|
|
Hypertension
|
3
|
2
|
|
Central and Peripheral Nervous System
|
|
Dizziness
|
21
|
11
|
|
Headache
|
17
|
12
|
|
Somnolence
|
5
|
3
|
|
Tremor
|
4
|
1
|
|
Gastrointestinal System
|
|
Nausea*
|
47
|
12
|
|
Vomiting*
|
31
|
6
|
|
Diarrhea
|
19
|
11
|
|
Anorexia***
|
17
|
3
|
|
Abdominal Pain
|
13
|
6
|
|
Dyspepsia
|
9
|
4
|
|
Psychiatric Disorders
|
|
Insomnia
|
9
|
7
|
|
Confusion
|
8
|
7
|
|
Depression
|
6
|
4
|
|
Anxiety
|
5
|
3
|
|
Hallucination
|
4
|
3
|
|
Aggressive Reaction
|
3
|
2
|
|
Resistance Mechanism Disorders
|
|
Urinary Tract Infection
|
7
|
6
|
*Nausea and Vomiting: In the controlled clinical
trials, 47% of the patients treated with an Exelon dose in the therapeutic
range of 6 mg to 12 mg per day (n=1189) developed nausea (compared with 12% in
placebo). A total of 31% of Exelon-treated patients developed at least 1
episode of vomiting (compared with 6% for placebo). The rate of vomiting was
higher during the titration phase (24% versus 3% for placebo) than in the
maintenance phase (14% versus 3% for placebo). The rates were higher in women
than men. Five percent of patients discontinued for vomiting, compared to less
than 1% for patients on placebo. Vomiting was severe in 2% of Exelon-treated
patients and was rated as mild or moderate each in 14% of patients. The rate of
nausea was higher during the titration phase (43% versus 9% for placebo) than
in the maintenance phase (17% versus 4% for placebo).
**Weight Decreased: In the controlled trials,
approximately 26% of women on high doses of Exelon (greater than 9 mg per day)
had weight loss equal to or greater than 7% of their baseline weight compared
to 6% in the placebo-treated patients. About 18% of the males in the high-dose
group experienced a similar degree of weight loss compared to 4% in
placebo-treated patients. It is not clear how much of the weight loss was
associated with anorexia, nausea, vomiting, and the diarrhea associated with
the drug.
***Anorexia: In the controlled clinical trials, of
the patients treated with an Exelon dose of 6 mg to 12 mg per day, 17%
developed anorexia compared to 3% of the placebo patients. Neither the time
course nor the severity of the anorexia is known.
Mild to Moderate Parkinson’s Disease
Dementia
Exelon has been administered to 779 individuals
during clinical trials worldwide. Of these, 663 patients have been treated for
at least 3 months, 476 patients have been treated for at least 6 months, and
313 patients have been treated for 1 year.
Most Common Adverse Reactions
The most common adverse reactions, defined as those
occurring at a frequency of at least 5% and twice the placebo rate, are largely
predicted by Exelon's cholinergic effects. These include nausea, vomiting,
tremor, anorexia, and dizziness.
Discontinuation Rates
The rate of discontinuation due to adverse events
in the single placebo-controlled trial of Exelon was 18% for patients receiving
3 mg to 12 mg per day compared to 11% for patients on placebo during the
24-week study.
The most frequent adverse reactions that led to
discontinuation from this study, defined as those occurring in at least 1% of
patients receiving Exelon and more frequent than those receiving placebo, were
nausea (3.6% Exelon versus 0.6% placebo), vomiting (1.9% Exelon versus 0.6%
placebo), and tremor (1.7% Exelon versus 0.0% placebo).
Adverse Reactions Observed at an
Incidence of at Least 2%
Table 3 lists adverse reactions that occurred in at
least 2% of patients in a single placebo-controlled trial and during the first
24 weeks of a 76-week open-label active-controlled trial for which the rate of
occurrence was greater for patients treated with Exelon doses of 3 mg to 12 mg
per day than for those treated with placebo in the placebo-controlled trial.
In general, adverse reactions were less frequent
later in the course of treatment.
Table 3: Proportion of Adverse Reactions Observed at a Frequency ≥2% and Occurring at Rate Greater than Placebo in
Clinical Trials
|
|
|
Active-Controlled
Study
|
Placebo-Controlled
Study
|
|
Body
System/Adverse Reaction
|
Exelon
(3 to 12
mg/day)
(n=294)
|
Exelon
(3 to 12
mg/day)
(n=362)
|
Placebo
(n=179)
|
|
Percent of Patients with any Adverse Event
|
88
|
84
|
71
|
|
|
|
Gastrointestinal Disorders
|
|
Nausea
|
38
|
29
|
11
|
|
Vomiting
|
13
|
17
|
2
|
|
Diarrhea
|
8
|
7
|
4
|
|
Upper
Abdominal Pain
|
4
|
4
|
1
|
|
Salivary
hypersecretion
|
2
|
1
|
0
|
|
General Disorders and Administrative Site
Conditions
|
|
Fall
|
10
|
6
|
6
|
|
Fatigue
|
5
|
4
|
3
|
|
Asthenia
|
4
|
2
|
1
|
|
Metabolism and Nutritional Disorders
|
|
Anorexia
|
-
|
6
|
3
|
|
Decreased
Appetite
|
5
|
8
|
5
|
|
Dehydration
|
1
|
2
|
1
|
|
Nervous System Disorders
|
|
Tremor
|
23
|
10
|
4
|
|
Dizziness
|
8
|
6
|
1
|
|
Headache
|
4
|
4
|
3
|
|
Somnolence
|
6
|
4
|
3
|
|
Parkinson’s
Disease (worsening)
|
-*
|
3
|
1
|
|
Bradykinesia
|
3
|
3
|
2
|
|
Dyskinesia
|
3
|
1
|
1
|
|
Cogwheel
rigidity
|
3
|
1
|
0
|
|
Hypokinesia
|
2
|
1
|
0
|
|
Parkinsonism
|
-
|
2
|
1
|
|
Psychiatric Disorders
|
|
Anxiety
|
4
|
4
|
1
|
|
Insomnia
|
2
|
3
|
2
|
|
Restlessness
|
1
|
3
|
2
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Increased
Sweating
|
2
|
2
|
1
|
*Parkinson’s disease (worsening) in the
active-controlled study was assessed by reported pre-identified adverse events
(tremor, cogwheel rigidity, fall), each of them listed with corresponding
frequencies.
Postmarketing Experience
The following adverse reactions have been
identified during post approval use of Exelon Capsules, Exelon Oral Solution,
or Exelon Patch. 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.
Cardiac Disorders: Tachycardia.
Hepatobiliary Disorders: Abnormal liver function
tests, hepatitis.
Nervous System Disorders: seizure.
Psychiatric Disorders: Aggression, nightmares.
Skin and Subcutaneous Tissue
Disorders:
Allergic dermatitis, application site hypersensitivity (patch), blister,
disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria.
7
DRUG INTERACTIONS
Metoclopramide
Due to the risk of additive
extrapyramidal adverse reactions, the concomitant use of metoclopramide and
Exelon is not recommended.
Cholinomimetic and Anticholinergic Medications
Exelon may increase the cholinergic
effects of other cholinomimetic medications and may also interfere with the
activity of anticholinergic medications (e.g., oxybutynin, tolterodine).
Concomitant use of Exelon with medications having these pharmacologic effects
is not recommended unless deemed clinically necessary [see Warnings and
Precautions (5.3)].
Beta-blockers
Additive bradycardic effects resulting in syncope
may occur when Exelon is used concomitantly with beta-blockers, especially
cardioselective beta-blockers (including atenolol). Concomitant use of Exelon
with beta-blockers is not recommended.
8
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
There are no adequate and
well-controlled studies in pregnant women. Reproduction studies conducted in
pregnant rats and rabbits at oral doses up to 2.3 mg-base/kg/day, or 2 (rat)
and 4 (rabbit) times the maximum recommended human dose (MRHD) of 12 mg per day
on a mg/m2basis, revealed no evidence of teratogenicity.
Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Rivastigmine and its metabolites are excreted in
rat milk following oral administration of rivastigmine; levels of rivastigmine
plus metabolites in rat milk are approximately 2 times that in maternal plasma.
It is not known whether rivastigmine is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from Exelon, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have
not been established. The use of Exelon in pediatric patients (below 18 years
of age) is not recommended.
Geriatric Use
Of the total number of patients in clinical studies
of Exelon, 86 % were 65 years and older while 46 % were 75 years and older. No
overall differences in safety or effectiveness were observed between these
patients and younger patients, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
Renal
Impairment
Patients with moderate to severe renal impairment
may be able to only tolerate lower doses [see
Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Hepatic Impairment
Patients with mild or moderate hepatic impairment
may be able to only tolerate lower doses [see
Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. No data are available on
the use of Exelon in patients with severe hepatic impairment.
Low or
High Body Weight
Because rivastigmine blood levels vary with weight,
careful titration and monitoring should be performed in patients with low or
high body weights [see Dosage and Administration (2.4),
Clinical Pharmacology (12.3)].
10
OVERDOSAGE
Because strategies for the management
of overdose are continually evolving, it is advisable to contact aPoisonControlCenterto determine the
latest recommendations for the management of an overdose of any drug.
As rivastigmine has a short plasma
half-life of about 1 hour and a moderate duration of acetylcholinesterase
inhibition of 8 to 10 hours, it is recommended that in cases of asymptomatic
overdoses, no further dose of Exelon should be administered for the next 24
hours.
As in any case of overdose, general
supportive measures should be utilized.
Overdosage with cholinesterase
inhibitors can result in cholinergic crisis characterized by severe nausea,
vomiting, salivation, sweating, bradycardia, hypotension, respiratory
depression, collapse and convulsions. Increasing muscle weakness is a
possibility and may result in death if respiratory muscles are involved.
Atypical responses in blood pressure and heart rate have been reported with
other drugs that increase cholinergic activity when coadministered with
quaternary anticholinergics such as glycopyrrolate. Additional symptoms
associated with rivastigmine overdose are diarrhea, abdominal pain, dizziness,
tremor, headache, somnolence, confusional state, hyperhidrosis, hypertension,
hallucinations and malaise. Due to the short half-life of rivastigmine,
dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be
clinically indicated in the event of an overdose.
In overdoses accompanied by severe
nausea and vomiting, the use of antiemetics should be considered. A fatal
outcome has been rarely reported with rivastigmine.
11 DESCRIPTION
Exelon (rivastigmine tartrate) is a
reversible cholinesterase inhibitor and is known chemically as
(S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate
hydrogen-(2R,3R)-tartrate. Rivastigmine tartrate is commonly referred to in the
pharmacological literature as SDZ ENA 713 or ENA 713. It has an empirical
formula of C14H22N2O2 •
C4H6O6 (hydrogen
tartrate salt-hta salt) and a molecular weight of 400.43 (hta salt).
Rivastigmine tartrate is a white to off-white, fine crystalline powder that is
very soluble in water, soluble in ethanol and acetonitrile, slightly soluble in
n-octanol and very slightly soluble in ethyl acetate.
The distribution coefficient at 37°C in
n-octanol/phosphate buffer solution pH 7 is 3.0.
Exelon Capsules contain rivastigmine tartrate,
equivalent to 1.5 mg, 3 mg, 4.5 mg, and 6 mg of rivastigmine base for oral
administration. Inactive ingredients are hydroxypropyl methylcellulose,
magnesium stearate, microcrystalline cellulose, and silicon dioxide. Each
hard-gelatin capsule contains gelatin, titanium dioxide and red and/or yellow
iron oxides.
Exelon Oral Solution is supplied as a solution
containing rivastigmine tartrate, equivalent to 2 mg/mL of rivastigmine base
for oral administration. Inactive ingredients are citric acid, D&C yellow
#10, purified water, sodium benzoate and sodium citrate.
12
CLINICAL PHARMACOLOGY
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.
Pharmacodynamics
After a 6-mg dose of rivastigmine,
anticholinesterase activity is present in cerebrospinal fluid (CSF) for about
10 hours, with a maximum inhibition of about 60% 5 hours after dosing.
In vitro and in vivo studies
demonstrate that the inhibition of cholinesterase by rivastigmine is not
affected by the concomitant administration of memantine, an
N-methyl-D-aspartate receptor antagonist.
Pharmacokinetics
Rivastigmine shows linear
pharmacokinetics up to 3 mg twice a day but is nonlinear at higher doses.
Doubling the dose from 3 mg to 6 mg twice a day results in a 3-fold increase in
AUC. The elimination half-life is about 1.5 hours, with most elimination as
metabolites via the urine.
Absorption
Rivastigmine is rapidly and completely absorbed.
Peak plasma concentrations are reached in approximately 1 hour. Absolute
bioavailability after a 3-mg dose is about 36%. Administration of Exelon with
food delays absorption (tmax) by 90 minutes lowers Cmax by approximately 30%
and increases AUC by approximately 30%.
Distribution
Rivastigmine is weakly bound to plasma proteins
(approximately 40%) over the therapeutic range. It readily crosses the
blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours.
It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg.
Metabolism
Rivastigmine is rapidly and extensively
metabolized, primarily via cholinesterase-mediated hydrolysis to the
decarbamylated metabolite. Based on evidence from in vitro and animal studies,
the major cytochrome P450 isozymes are minimally involved in rivastigmine
metabolism. Consistent with these observations is the finding that no drug
interactions related to cytochrome P450 have been observed in humans.
Elimination
The major pathway of elimination is via the
kidneys. Following administration of 14C-rivastigmine to 6 healthy
volunteers, total recovery of radioactivity over 120 hours was 97% in urine and
0.4% in feces. No parent drug was detected in urine. The sulfate conjugate of
the decarbamylated metabolite is the major component excreted in urine and
represents 40% of the dose. Mean oral clearance of rivastigmine is 1.8 ± 0.6
L/min after 6 mg twice a day.
Age
Following a single 2.5-mg oral dose to elderly
volunteers (60 years and older, n=24) and younger volunteers (n=24), mean oral clearance
of rivastigmine was 30% lower in elderly (7 L/min) than in younger subjects (10
L/min).
Gender and Race
Population pharmacokinetic analysis of oral
rivastigmine indicated that neither gender (n=277 males and 348 females) nor
race (n=575 Caucasian, 34 Black, 4 Asian, and 12 Other) affected clearance of
the drug.
Body Weight
A relationship between drug exposure at
steady-state (rivastigmine and metabolite NAP226-90) and body weight was
observed in Alzheimer’s dementia patients. Rivastigmine exposure is higher in
subjects with low body weight. Compared to a patient with a body weight of 65
kg, the rivastigmine steady-state concentrations in a patient with a body
weight of 35 kg would be approximately doubled, while for a patient with a body
weight of 100 kg the concentrations would be approximately halved.
Renal Impairment
Following a single 3-mg dose, mean oral clearance
of rivastigmine is 64% lower in moderately impaired renal patients (n=8, GFR=10
to 50 mL/min) than in healthy subjects (n=10, GFR ≥60 mL/min); Cl/F=1.7 L/min
and 4.8 L/min, respectively. In patients with severe renal impairment (n=8, GFR
<10 mL/min), mean oral clearance of rivastigmine is 43% higher than in
healthy subjects (n=10, GFR ≥60 mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively.
For unexplained reasons, the severely impaired renal patients had a higher
clearance of rivastigmine than moderately impaired patients.
Hepatic Impairment
Following a single 3-mg dose, mean oral clearance
of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy
proven) than in healthy subjects (n=10). After multiple 6-mg twice a day oral
dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7,
Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically
impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects
(n=10).
Smoking
Following oral rivastigmine administration (up to
12 mg per day) with nicotine use, population pharmacokinetic analysis showed
increased oral clearance of rivastigmine by 23% (n=75 smokers and 549
nonsmokers).
Drug Interaction Studies
Effect of Rivastigmine on the
Metabolism of Other Drugs
Rivastigmine is primarily metabolized through
hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450
isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions
with drugs metabolized by the following isoenzyme systems are expected: CYP1A2,
CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6.
No pharmacokinetic interaction was observed between
rivastigmine taken orally and digoxin, warfarin, diazepam or fluoxetine in
studies in healthy volunteers. The increase in prothrombin time induced by
warfarin is not affected by administration of rivastigmine.
Effect of Other Drugs on the
Metabolism of Rivastigmine
Drugs that induce or inhibit CYP450 metabolism are
not expected to alter the metabolism of rivastigmine.
Population pharmacokinetic analysis with a database
of 625 patients showed that the pharmacokinetics of rivastigmine taken orally
were not influenced by commonly prescribed medications such as antacids (n=77),
antihypertensives (n=72), beta-blockers (n=42), calcium channel blockers
(n=75), antidiabetics (n=21), NSAIDs (n=79), estrogens (n=70), salicylate
analgesics (n=177), antianginals (n=35) and antihistamines (n=15).
13
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In oral carcinogenicity studies conducted at doses
up to 1.1 mg-base/kg/day in rats and 1.6 mg-base/kg/day in mice, rivastigmine
was not carcinogenic. These doses are less than the maximum recommended human
dose (MRHD) of 12 mg per day on a mg/m2 basis.
Mutagenesis
Rivastigmine was clastogenic in in vitro
chromosomal aberration assays in mammalian cells in the presence, but not the
absence, of metabolic activation. Rivastigmine was negative in an in vitro
bacterial reverse mutation (Ames)
assay, an in vitro HGPRT assay, and in an in vivo mouse micronucleus test.
Impairment of Fertility
Rivastigmine had no effect on fertility or
reproductive performance in rats at oral doses up to 1.1 mg-base/kg/day, a dose
less than the MRHD on a mg/m2 basis.
14
CLINICAL STUDIES
Mild to Moderate Alzheimer’s Disease
The effectiveness of Exelon as a treatment for
Alzheimer's disease is demonstrated by the results of 2 randomized,
double-blind, placebo-controlled clinical investigations (Study 1 and Study 2)
in patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV
criteria, Mini-Mental State Examination (MMSE) ≥10 and ≤26, and the Global
Deterioration Scale (GDS)]. The mean age of patients participating in Exelon
trials was 73 years with a range of 41 to 95. Approximately 59% of patients
were women and 41% were men. The racial distribution was Caucasian 87%, Black
4%, and other races 9%.
In each study, the effectiveness of Exelon was
evaluated using a dual outcome assessment strategy.
The ability of Exelon to improve cognitive
performance was assessed with the cognitive subscale of the Alzheimer's Disease
Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively
validated in longitudinal cohorts of Alzheimer's disease patients. The ADAS-cog
examines selected aspects of cognitive performance including elements of
memory, orientation, attention, reasoning, language, and praxis. The ADAS-cog
scoring range is from 0 to 70, with higher scores indicating greater cognitive
impairment. Elderly normal adults may score as low as 0 or 1, but it is not
unusual for non-demented adults to score slightly higher.
The patients recruited as participants in each
study had mean scores on ADAS-cog of approximately 23 units, with a range from
1 to 61. Experience gained in longitudinal studies of ambulatory patients with
mild to moderate Alzheimer's disease suggests that they gain 6 to 12 units a
year on the ADAS-cog. Lesser degrees of change, however, are seen in patients
with very mild or very advanced disease because the ADAS-cog is not uniformly
sensitive to change over the course of the disease. The annualized rate of
decline in the placebo patients participating in Exelon trials was
approximately 3 to 8 units per year.
The ability of Exelon to produce an overall
clinical effect was assessed using a Clinician's Interview-Based Impression of
Change (CIBIC) that required the use of caregiver information, the CIBIC-Plus.
The CIBIC-Plus is not a single instrument and is not a standardized instrument
like the ADAS-cog. Clinical trials for investigational drugs have used a
variety of CIBIC formats, each different in terms of depth and structure. As
such, results from a CIBIC-Plus reflect clinical experience from the trial or
trials in which it was used and cannot be compared directly with the results of
CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in the
Exelon trials was a structured instrument based on a comprehensive evaluation
at baseline and subsequent time-points of 3 domains: patient cognition,
behavior and functioning, including assessment of activities of daily living.
It represents the assessment of a skilled clinician using validated scales
based on his/her observation at interviews conducted separately with the
patient and the caregiver familiar with the behavior of the patient over the
interval rated. The CIBIC-Plus is scored as a 7-point categorical rating,
ranging from a score of 1, indicating "markedly improved," to a score
of 4, indicating "no change" to a score of 7, indicating "marked
worsening." The CIBIC-Plus has not been systematically compared directly
to assessments not using information from caregivers or other global methods.
U.S.26-Week Study of Exelon in Mild to Moderate Alzheimer’s Disease (Study 1)
In a study of 26 weeks duration, 699 patients were
randomized to either a dose range of 1 mg to 4 mg or 6 mg to 12 mg of Exelon
per day or to placebo, each given in divided doses. The 26-week study was
divided into a 12-week forced-dose titration phase and a 14-week maintenance
phase. The patients in the active treatment arms of the study were maintained
at their highest tolerated dose within the respective range.
Figure 1 illustrates the time course for the change
from baseline in ADAS-cog scores for all 3 dose groups over the 26 weeks of the
study. At 26 weeks of treatment, the mean differences in the ADAS-cog change
scores for the Exelon-treated patients compared to the patients on placebo were
1.9 and 4.9 units for the 1 mg to 4 mg and 6 mg to 12 mg treatments, respectively.
Both treatments were statistically significantly superior to placebo and the 6
mg to 12 mg per day range was significantly superior to the 1 mg to 4 mg per
day range.
Figure 1: Time-course of the Change
from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment
in Study 1
Figure 2 illustrates the cumulative percentages of
patients from each of the 3 treatment groups who had attained at least the
measure of improvement in ADAS-cog score shown on the x-axis. Three change
scores, (7-point and 4-point reductions from baseline or no change in score)
have been identified for illustrative purposes, and the percent of patients in
each group achieving that result is shown in the inset table.
The curves demonstrate that both patients assigned
to Exelon and placebo have a wide range of responses, but that the Exelon
groups are more likely to show the greater improvements. A curve for an
effective treatment would be shifted to the left of the curve for placebo,
while an ineffective or deleterious treatment would be superimposed upon, or
shifted to the right of the curve for placebo, respectively.
Figure 2: Cumulative Percentage of
Patients Completing 26 Weeks of Double-blind Treatment with Specified Changes
from Baseline ADAS-cog Scores. The Percentages of Randomized Patients who
Completed the Study were: Placebo 84%, 1 mg-4 mg 85%, and 6 mg-12 mg 65%.
Figure 3 is a histogram of the frequency
distribution of CIBIC-Plus scores attained by patients assigned to each of the
3 treatment groups who completed 26 weeks of treatment. The mean Exelon-placebo
differences for these groups of patients in the mean rating of change from
baseline were 0.32 units and 0.35 units for 1 mg to 4 mg and 6 mg to 12 mg of
Exelon, respectively. The mean ratings for the 6 mg to 12 mg per day and 1 mg
to 4 mg per day groups were statistically significantly superior to placebo.
The differences between the 6 mg to 12 mg per day and the 1 mg to 4 mg per day
groups were statistically significant.
Figure 3: Frequency Distribution of
CIBIC-Plus Scores at Week 26 in Study 1
Global 26-Week Study in Mild to
Moderate Alzheimer’s Disease (Study 2)
In a second study of 26 weeks duration, 725
patients were randomized to either a dose range of 1 mg to 4 mg or 6 mg to 12
mg of Exelon per day or to placebo, each given in divided doses. The 26-week
study was divided into a 12-week forced-dose titration phase and a 14-week
maintenance phase. The patients in the active treatment arms of the study were
maintained at their highest tolerated dose within the respective range.
Figure 4 illustrates the time course for the change
from baseline in ADAS-cog scores for all 3 dose groups over the 26 weeks of the
study. At 26 weeks of treatment, the mean differences in the ADAS-cog change
scores for the Exelon-treated patients compared to the patients on placebo were
0.2 and 2.6 units for the 1 mg to 4 mg and 6 mg to 12 mg treatments,
respectively. The 6 mg to 12 mg per day group was statistically significantly
superior to placebo, as well as to the 1 mg to 4 mg per day group. The
difference between the 1 mg to 4 mg per day group and placebo was not
statistically significant.
Figure 4: Time-course of the Change
from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment
Figure 5 illustrates the cumulative percentages of
patients from each of the 3 treatment groups who had attained at least the
measure of improvement in ADAS-cog score shown on the x-axis. Similar to the
U.S. 26-week study, the curves demonstrate that both patients assigned to
Exelon and placebo have a wide range of responses, but that the 6 mg to 12 mg
per day Exelon group is more likely to show the greater improvements.
Figure 5: Cumulative Percentage of
Patients Completing 26 Weeks of Double-blind Treatment with Specified Changes
from Baseline ADAS-cog Scores. The Percentages of Randomized Patients who
Completed the Study were: Placebo 87%, 1 mg-4 mg 86%, and 6 mg-12 mg 67%.
Figure 6 is a histogram of the frequency
distribution of CIBIC-Plus scores attained by patients assigned to each of the
3 treatment groups who completed 26 weeks of treatment. The mean Exelon-placebo
differences for these groups of patients for the mean rating of change from
baseline were 0.14 units and 0.41 units for 1 mg to 4 mg and 6 mg to 12 mg of
Exelon, respectively. The mean ratings for the 6 mg to 12 mg per day group were
statistically significantly superior to placebo. The comparison of the mean
ratings for the 1 mg to 4 mg per day group and placebo group was not
statistically significant.
Figure 6: Frequency Distribution of
CIBIC-Plus Scores at Week 26 in Study 2
U.S.Fixed-Dose Study in Mild to Moderate Alzheimer’s Disease (Study 3)
In a study of 26 weeks duration, 702 patients were
randomized to doses of 3 mg, 6 mg, or 9 mg per day of Exelon or to placebo,
each given in divided doses. The fixed-dose study design, which included a
12-week forced-dose titration phase and a 14-week maintenance phase, led to a
high dropout rate in the 9 mg per day group because of poor tolerability. At 26
weeks of treatment, significant differences were observed for the ADAS-cog mean
change from baseline for the 9 mg per day and 6 mg per day groups, compared to
placebo. No significant differences were observed between any of the
Exelon-dose groups and placebo for the analysis of the CIBIC-Plus mean rating
of change. Although no significant differences were observed between Exelon
treatment groups, there was a trend toward numerical superiority with higher
doses.
Mild to Moderate Parkinson’s Disease
Dementia
International 24-Week Study (Study 4)
The effectiveness of Exelon as a treatment for
dementia associated with Parkinson’s disease is demonstrated by the results of
1 randomized, double-blind, placebo-controlled clinical investigation in
patients with mild to moderate dementia, with onset at least 2 years after the
initial diagnosis of idiopathic Parkinson’s disease. The diagnosis of
idiopathic Parkinson’s disease was based on the United Kingdom Parkinson’s
Disease Society Brain Bank clinical criteria. The diagnosis of dementia was
based on the criteria stipulated under the DSM-IV category “Dementia Due To
Other General Medical Condition” (code 294.1x), but patients were not required
to have a distinctive pattern of cognitive deficits as part of the dementia.
Alternate causes of dementia were excluded by clinical history, physical and
neurological examination, brain imaging, and relevant blood tests. Patients
enrolled in the study had a MMSE score ≥10 and ≤24 at entry. The mean age of
patients participating in this trial was 72.7 years with a range of 50–91
years. Approximately, 35.1% of patients were women and 64.9% of patients were
men. The racial distribution was 99.6% Caucasian and other races 0.4%.
This study used a dual outcome assessment strategy
to evaluate the effectiveness of Exelon.
The ability of Exelon to improve cognitive
performance was assessed with the ADAS-cog.
The ability of Exelon to produce an overall
clinical effect was assessed using the Alzheimer’s Disease Cooperative Study –
Clinician’s Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more
standardized form of CIBIC-Plus and is also scored as a 7-point categorical
rating, ranging from a score of 1, indicating "markedly improved," to
a score of 4, indicating "no change" to a score of 7, indicating
"marked worsening".
In this study, 541 patients were randomized to a
dose range of 3 mg to 12 mg of Exelon per day or to placebo in a ratio of 2:1,
given in divided doses. The 24-week study was divided into a 16-week titration
phase and an 8-week maintenance phase. The patients in the active treatment arm
of the study were maintained at their highest tolerated dose within the specified
dose range.
Figure 7 illustrates the time course for the change
from baseline in ADAS-cog scores for both treatment groups over the 24-week
study. At 24 weeks of treatment, the mean difference in the ADAS-cog change
scores for the Exelon-treated patients compared to the patients on placebo was
3.8 points. This treatment difference was statistically significant in favor of
Exelon when compared to placebo.
Figure 7: Time Course of the Change
from Baseline in ADAS-cog Score for Patients Completing 24 Weeks of Treatment
in Study 4
Figure 8 is a histogram of the distribution of
patients’ scores on the ADCS-CGIC (Alzheimer’s Disease Cooperative Study -
Clinician’s Global Impression of Change) at 24 weeks. The mean difference in
change scores between the Exelon and placebo groups from baseline was 0.5
points. This difference was statistically significant in favor of Exelon treatment.
Figure 8: Distribution of
ADCS-CGIC Scores for Patients Completing 24 Weeks of Treatment in Study 4
Patients’ age, gender, or race did not predict
clinical outcome of Exelon treatment.
16
HOW SUPPLIED/STORAGE AND HANDLING
Exelon Capsules
Exelon (rivastigmine tartrate) Capsules 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.
Bottles of 60
NDC 0078-0323-44
Bottles of 500
NDC 0078-0323-08
Unit Dose (blister
pack) Box of 100 (strips of 10) NDC 0078-0323-06
3 mg capsule – orange, “Exelon 3 mg” is printed in
red on the body of the capsule.
Bottles of 60
NDC 0078-0324-44
Bottles of 500
NDC 0078-0324-08
Unit Dose (blister
pack) Box of 100 (strips of 10) NDC 0078-0324-06
4.5 mg capsule – red, “Exelon 4,5 mg” is printed in
white on the body of the capsule.
Bottles of 60
NDC 0078-0325-44
Bottles of 500
NDC 0078-0325-08
Unit Dose (blister
pack) Box of 100 (strips of 10) NDC 0078-0325-06
6 mg capsule – orange and red, “Exelon 6 mg” is
printed in red on the body of the capsule.
Bottles of 60
NDC 0078-0326-44
Bottles of 500
NDC 0078-0326-08
Unit Dose (blister
pack) Box of 100 (strips of 10) NDC 0078-0326-06
Store at 25°C (77°F); excursions permitted to
15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Store in a tight
container.
Exelon Oral Solution
Exelon (rivastigmine tartrate) Oral Solution is
supplied as 120 mL of a clear, yellow solution (2 mg/mL base) in a 4-ounce USP
Type III amber glass bottle with a child-resistant 19-mm linerless cap, dip
tube and self-aligning plug. The oral solution is packaged with a dispenser set
which consists of an assembled oral dosing syringe that allows dispensing a
maximum volume of 3 mL corresponding to a 6-mg dose, with a plastic tube
container.
Bottles of 120 mL
NDC 0078-0339-31
Store at 25°C (77°F); excursions permitted to
15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Store in an upright
position and protect from freezing.
When Exelon Oral Solution is combined with cold
fruit juice or soda, the mixture is stable at room temperature for up to 4
hours.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the
FDA-approved patient labeling (Instructions for Use).
Gastrointestinal Adverse Reactions
Caregivers should be advised of the high incidence
of nausea and vomiting associated with the use of the drug along with the
possibility of anorexia and weight loss. Caregivers should be encouraged to
monitor for these adverse events and inform the physician if they occur. It is
critical to inform caregivers that if therapy has been interrupted for more
than several days, the next dose should not be administered until they have
discussed this with the physician [see
Warnings and Precautions (5.1)].
Skin Reactions
Caregivers and patients should be advised that
allergic skin reactions have been reported in association with Exelon
regardless of formulation (capsules, oral solution or transdermal patch). In
case of skin reaction while taking Exelon, patients should consult with their
physician immediately [see Warnings and Precautions (5.2)].
Importance of Correct Usage
Caregivers should be instructed in the correct
procedure for administering Exelon Oral Solution. In addition, they should be
informed of the existence of an Instruction Sheet (included with the product)
describing how the solution is to be administered. They should be urged to read
this sheet prior to administering Exelon Oral Solution. Caregivers should
direct questions about the administration of the solution to either their
physician or pharmacist. See Exelon Oral Solution Instructions for Use.
Concomitant Use of Drugs with Cholinergic
Action
Caregivers and patients should be advised that
cholinomimetics, including rivastigmine, may exacerbate or induce
extrapyramidal symptoms. Worsening in patients with Parkinson’s disease,
including an increased incidence or intensity of tremor, has been
observed [see Warnings and Precautions (5.3)].
T2016-94
November 2016
Instructions for Use
Exelon (ECS-‘el-on)
(rivastigmine tartrate)
Oral Solution
Instructions for using your Exelon
Oral Solution
Read these instructions before taking Exelon Oral
Solution and each time you get a refill. There may be new information. This
information does not take the place of talking to your doctor about your
medical condition or your treatment.
Preparing your dose of Exelon Oral Solution.
You will need the following supplies:
Exelon Oral Solution BottleOral dosing syringe in protective
case
|
1.
|
Remove
the oral dosing syringe from its protective case.
|
|
2.
|
Firmly
push down and twist the child-resistant cap counter-clockwise to open the
bottle.
|
|
3.
|
Keep
the bottle upright on a firm table and insert tip of syringe into the opening
of the white stopper.
|
|
4.
|
While
holding the syringe in place, pull the plunger of the syringe up to the level
(see markings on side of syringe) that equals the dose prescribed by your
doctor.
|
|
5.
|
Before
removing syringe with your prescribed dose from the bottle, push out any
large bubbles by moving plunger up and down a few times.
• After the large bubbles are gone, pull the plunger again to the level that
equals the dose prescribed by your doctor.
• Do not worry about a few tiny bubbles. This will not affect your dose.
|
|
6.
|
Remove
the syringe from the bottle. You may swallow Exelon Oral Solution from the
syringe or mix it with a small glass of water, cold fruit juice or soda.
|
|
|
• If mixing with water,
cold fruit juice or soda, be sure to stir completely and to drink the all of
the liquid.
• Do not mix Exelon Oral Solution with liquids other than water, cold fruit
juice, or soda.
|
|
mixing with liquid
|
|
|
|
7.
|
After
use, rinse the empty syringe by inserting the open end of the syringe into a
glass of water. Pull the plunger out to draw in water, and push the plunger
in to remove the water. Repeat this several times. Allow the syringe to air
dry and put it back into its case.
|
|
8.
|
Place
the child-resistant cap back on the bottle and store in an upright position.
|
How to Store Exelon Oral Solution:
Store at room temperature between
68°F to 77°F (20°C to 25°C) in an upright position.After mixing with water, cold fruit
juice, or soda, Exelon Oral Solution can be stored at room temperature for
up to 4 hours before drinking.Do not store in freezer.
This Instructions for Use has been approved by the
U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover,New Jersey07936
© Novartis
T2013-86
October 2013
