Disclaimer:
Medidex is not a provider of medical services and all information is provided for the convenience of the user. No medical decisions should be made based on the information provided on this website without first consulting a licensed healthcare provider.This website is intended for persons 18 years or older. No person under 18 should consult this website without the permission of a parent or guardian.
Exelon
Overview
What is Exelon?
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 CHNO • CHO (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.
ExelonCapsules contain rivastigmine tartrate, equivalent
to 1.5, 3, 4.5 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.
What does Exelon look like?
What are the available doses of Exelon?
Sorry No records found.
What should I talk to my health care provider before I take Exelon?
Sorry No records found
How should I use Exelon?
Exelon (rivastigmine tartrate) is
indicated for the treatment of mild to moderate dementia of the Alzheimer's
type.
Exelon (rivastigmine tartrate) is indicated for
the treatment of mild to moderate dementia associated with Parkinson’s
disease.
The dementia of Parkinson’s disease is purportedly characterized by
impairments in executive function, memory retrieval, and attention in patients
with an established diagnosis of Parkinson’s disease. The diagnosis of the
dementia of Parkinson’s disease, however, can reliably be made in patients in
whom a progressive dementia syndrome occurs (without the necessity to document
the specific deficits described above) at least 2 years after a diagnosis of
Parkinson’s disease has been made, and in whom other causes of dementia have
been ruled out (see CLINICAL PHARMACOLOGY, Clinical Trial Data).
Dementia of the Alzheimer’s
T
ype
The dosage of Exelon (rivastigmine tartrate) shown to
be effective in controlled clinical trials in Alzheimer’s disease is 6-12
mg/day, given as twice-a-day dosing (daily doses of 3 to 6 mg BID). There is
evidence from the clinical trials that doses at the higher end of this range may
be more beneficial.
The starting dose of Exelon is 1.5 mg twice a day (BID). If this dose
is well tolerated, after a minimum of 2 weeks of treatment, the dose may be
increased to 3 mg BID. Subsequent increases to 4.5 mg BID and 6 mg BID should be
attempted after a minimum of 2 weeks at the previous dose. 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
treatment is interrupted for longer than several days, treatment should be
reinitiated with the lowest daily dose and titrated as described above (see
WARNINGS). The maximum dose is 6 mg BID (12 mg/day).
Dementia
A
ssociated with Parkinson’s Disease
The dosage of Exelon shown to be effective in the single controlled clinical
trial conducted in dementia associated with Parkinson’s disease is 3-12 mg/day,
given as twice-a-day dosing (daily doses of 1.5-6 mg BID). In that medical
condition, the starting dose of Exelon is 1.5 mg BID; subsequently, the dose may
be increased to 3 mg BID and further to 4.5 mg BID and 6 mg BID, based on
tolerability, with a minimum of 4 weeks at each dose.
Exelon should be taken with meals in divided doses in the morning and
evening.
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 PRECAUTIONS: Information for Patients
and Caregivers).
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.
What interacts with Exelon?
Exelon (rivastigmine tartrate) is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation (see DESCRIPTION).
What are the warnings of Exelon?
Doses of 0.8 mg/kg/day (9.4 mg/m/day) in rabbits,
1000 mg/kg/day (7000 mg/m/day) in rats, and 25 mg/kg/day
(295 mg/m/day) in cynomolgus monkeys did not produce
teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and
2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human
dose of 4 mg based on body-weight and body-surface-area, respectively assuming a
50 kg woman.
Peptic Ulcers/Gastrointestinal Bleeding:
Exelon as a cholinesterase inhibitor, is likely to exaggerate
succinylcholine-type muscle relaxation during anesthesia.
Drugs that increase cholinergic activity may have vagotonic
effects on heart rate (e.g., bradycardia). The potential for this action may be
particularly important to patients with "sick sinus syndrome" or other
supraventricular cardiac conduction conditions. In clinical trials, Exelon was
not associated with any increased incidence of cardiovascular adverse events,
heart rate or blood pressure changes, or ECG abnormalities. Syncopal episodes
have been reported in 3% of patients receiving 6-12 mg/day of Exelon, compared
to 2% of placebo patients.
Although this was not observed in clinical trials of Exelon,
drugs that increase cholinergic activity may cause urinary obstruction.
Seizures:
Like other drugs that increase cholinergic activity, Exelon
should be used with care in patients with a history of asthma or obstructive
pulmonary disease.
What are the precautions of Exelon?
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.
Caregivers should be instructed in the correct procedure for
administering Exelon
(rivastigmine tartrate) 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.
Caregivers and patients should be advised that like other
cholinomimetics, Exelon may exacerbate or induce
extrapyramidal symptoms. Worsening in patients with Parkinson’s disease,
including an increased incidence or intensity of tremor, has been
observed.
Effect of Exelon on the Metabolism of
Other Drugs:
No pharmacokinetic interaction was observed between rivastigmine and
digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The
elevation of prothrombin time induced by warfarin is not affected by
administration of Exelon.
Effect of Other Drugs on the Metabolism of
Exelon:
Population PK analysis with a database of 625 patients showed that the
pharmacokinetics of rivastigmine were not influenced by commonly prescribed
medications such as antacids (n=77), antihypertensives (n=72), ß-blockers
(n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal
antiinflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177),
antianginals (n=35), and antihistamines (n=15).
Use with Anticholinergics:
Use with Cholinomimetics and Other Cholinesterase
Inhibitors:
In carcinogenicity studies conducted at dose levels up to 1.1
mg-base/kg/day in rats and 1.6 mg-base/kg/day in mice, rivastigmine was not
carcinogenic. These dose levels are approximately 0.9 times and 0.7 times the
maximum recommended human daily dose of 12 mg/day on a mg/m basis.
Rivastigmine was clastogenic in two in vitro assays in the presence,
but not the absence, of metabolic activation. It caused structural chromosomal
aberrations in V79 Chinese hamster lung cells and both structural and numerical
(polyploidy) chromosomal aberrations in human peripheral blood lymphocytes.
Rivastigmine was not genotoxic in three in vitro assays: the Ames test, the
unscheduled DNA synthesis (UDS) test in rat hepatocytes (a test for induction of
DNA repair synthesis), and the HGPRT test in V79 Chinese hamster cells.
Rivastigmine was not clastogenic in the in vivo mouse micronucleus test.
Rivastigmine had no effect on fertility or reproductive performance in
the rat at dose levels up to 1.1 mg-base/kg/day. This dose is approximately 0.9
times the maximum recommended human daily dose of 12 mg/day on a mg/m basis.
Pregnancy Category B:
It is not known whether rivastigmine is excreted in human breast
milk. Exelon has no indication for use in nursing mothers.
There are no adequate and well-controlled trials documenting the
safety and efficacy of Exelon in any illness occurring in children.
What are the side effects of Exelon?
The rate of discontinuation due to adverse events in controlled
clinical trials of Exelon (rivastigmine tartrate) was
15% for patients receiving 6-12 mg/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 events 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.
The most common adverse events, 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.
Exelon use is associated with significant nausea, vomiting, and
weight loss (see WARNINGS).
Table 2 lists treatment-emergent signs and symptoms that were
reported 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
6-12 mg/day than for those treated with placebo. The prescriber should be aware
that these figures cannot be used to predict the frequency of adverse events in
the course of usual medical practice when patient characteristics and other
factors may differ from those prevailing during clinical studies. Similarly, the
cited frequencies cannot be directly compared with figures obtained from other
clinical investigations involving different treatments, uses, or investigators.
An inspection of these frequencies, however, does provide the prescriber with
one basis by which to estimate the relative contribution of drug and non-drug
factors to the adverse event incidences in the population studied.
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 events in the controlled studies. Nausea, vomiting and
weight loss were more frequent in women than men.
Other adverse events observed at a rate of 2% or more on Exelon 6-12
mg/day but at a greater or equal rate on placebo were chest pain, peripheral
edema, vertigo, back pain, arthralgia, pain, bone fracture, agitation,
nervousness, delusion, paranoid reaction, upper respiratory tract infection,
infection (general), coughing, pharyngitis, bronchitis, rash (general), urinary
incontinence.
The rate of discontinuation due to adverse events in the single
controlled trial of Exelon (rivastigmine tartrate) was 18.2% for patients
receiving 3-12 mg/day compared to 11.2% for patients on placebo during the
24-week study.
The most frequent adverse events 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 vs.
0.6% placebo), vomiting (1.9% Exelon vs. 0.6% placebo), and tremor (1.7% Exelon
vs. 0.0% placebo).
The most common adverse events, 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.
Table 3 lists treatment-emergent signs and symptoms that were
reported 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
3-12 mg/day than for those treated with placebo. The prescriber should be aware
that these figures cannot be used to predict the frequency of adverse events in
the course of usual medical practice when patient characteristics and other
factors may differ from those prevailing during clinical studies. Similarly, the
cited frequencies cannot be directly compared with figures obtained from other
clinical investigations involving different treatments, uses, or investigators.
An inspection of these frequencies, however, does provide the prescriber with
one basis by which to estimate the relative contribution of drug and non-drug
factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of
treatment.
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 10-12 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.
Treatment-emergent signs and symptoms that occurred during 8 controlled
clinical trials and 9 open-label trials in North America, Western Europe,
Australia, South Africa, and Japan were recorded as adverse events by the
clinical investigators using terminology of their own choosing. To provide an
overall estimate of the proportion of individuals having similar types of
events, the events were grouped into a smaller number of standardized categories
using a modified WHO dictionary, and event frequencies were calculated across
all studies. These categories are used in the listing below. The frequencies
represent the proportion of 5,297 patients from these trials who experienced
that event while receiving Exelon. All adverse events occurring in at least 6
patients (approximately 0.1%) are included, except for those already listed
elsewhere in labeling, WHO terms too general to be informative, relatively minor
events, or events unlikely to be drug-caused. Events are classified by body
system and listed using the following definitions: frequent adverse events –
those occurring in at least 1/100 patients; infrequent adverse events – those
occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily
related to Exelon treatment and in most cases were observed at a similar
frequency in placebo-treated patients in the controlled studies.
Autonomic Nervous System:
Infrequent:
Body as a Whole:
Frequent:
Infrequent:
Cardiovascular System:
Frequent:
Central and Peripheral Nervous System:
Frequent:
Infrequent:
Endocrine System:
Infrequent:
Gastrointestinal System:
Frequent:
Infrequent:
Hearing and Vestibular Disorders:
Frequent:
Heart Rate and Rhythm Disorders:
Frequent:
Infrequent:
Liver and Biliary System Disorders:
Infrequent:
Metabolic and Nutritional Disorders:
Frequent:
Infrequent:
Musculoskeletal Disorders:
Frequent:
Infrequent:
Myo-, Endo-, Pericardial and Valve
Disorders:
Frequent:
Platelet, Bleeding, and Clotting
Disorders:
Frequent:
I
nfrequent:
Psychiatric Disorders:
Frequent:
Infrequent:
Red Blood Cell Disorders:
Frequent:
Infrequent:
Reproductive Disorders (Female and
Male):
Infrequent:
Resistance Mechanism Disorders:
Infrequent:
Respiratory System:
Infrequent:
Skin and Appendages:
Frequent:
Infrequent:
Special Senses:
Infrequent:
Urinary System Disorders:
Frequent:
Infrequent:
Vascular (extracardiac) Disorders:
Infrequent:
Vision Disorders:
Frequent:
Infrequent:
White Cell and Resistance Disorders:
Infrequent:
Exelon has been administered to 485 individuals during clinical
trials worldwide. Of these, 413 patients have been treated for at least 3
months, 253 patients have been treated for at least 6 months, and 113 patients
have been treated for 1 year.
Additional treatment-emergent adverse events in patients with
Parkinson’s disease dementia occurring in at least 1 patient (approximately
0.3%) are listed below, excluding events that are already listed above for the
dementia of the Alzheimer’s type or elsewhere in labeling, WHO terms too general
to be informative, relatively minor events, or events unlikely to be
drug-caused. Events are classified by body system and listed using the following
definitions: frequent adverse events – those occurring in at least 1/100
patients; infrequent adverse events – those occurring in 1/100 to 1/1,000
patients. These adverse events are not necessarily related to Exelon treatment
and in most cases were observed at a similar frequency in placebo-treated
patients in the controlled studies.
Cardiovascular System:
Frequent:
Infrequent:
Central and Peripheral Nervous System:
Frequent:
Infrequent:
Endocrine System:
Infrequent:
Gastrointestinal System:
Frequent:
Infrequent:
Hearing and Vestibular Disorders:
Frequent:
Infrequent:
Heart Rate and Rhythm Disorders:
Infrequent:
Liver and Biliary System Disorders:
Infrequent:
Musculoskeletal Disorders:
Frequent:
Infrequent:
Psychiatric Disorders:
Frequent:
Infrequent:
Reproductive Disorders (Female and
Male):
Infrequent:
Respiratory System:
Frequent:
Infrequent:
Urinary System Disorders:
Infrequent:
Vascular (extracardiac) Disorders:
Infrequent:
Vision Disorders:
Infrequent:
Voluntary reports of adverse events temporally associated with
Exelon that have been received since market introduction that are not listed
above, and that may or may not be causally related to the drug include the
following:
Skin and Appendages:
| Study Phase | Titration | Maintenance | Overall | |||
| Placebo | Placebo | Placebo | ||||
| (n=868) | (n=1,189) | (n=788) | (n=987) | (n=868) | (n=1,189) | |
| Nausea | less than 1 | 8 | less than 1 | 1 | 1 | 8 |
| Vomiting | less than 1 | 4 | less than 1 | 1 | less than 1 | 5 |
| Anorexia | 0 | 2 | less than 1 | 1 | less than 1 | 3 |
| Dizziness | less than 1 | 2 | less than 1 | 1 | less than 1 | 2 |
| Body System/Adverse Event | ||||||
| Percent of Patients with any Adverse Event | 79 | 92 | ||||
| Sweating Increased | 1 | 4 | ||||
| Syncope | 2 | 3 | ||||
| Accidental Trauma | 9 | 10 | ||||
| Fatigue | 5 | 9 | ||||
| Asthenia | 2 | 6 | ||||
| Malaise | 2 | 5 | ||||
| Influenza-like Symptoms | 2 | 3 | ||||
| Weight Decrease | less than 1 | 3 | ||||
| Hypertension | 2 | 3 | ||||
| Dizziness | 11 | 21 | ||||
| Headache | 12 | 17 | ||||
| Somnolence | 3 | 5 | ||||
| Tremor | 1 | 4 | ||||
| Nausea | 12 | 47 | ||||
| Vomiting | 6 | 31 | ||||
| Diarrhea | 11 | 19 | ||||
| Anorexia | 3 | 17 | ||||
| Abdominal Pain | 6 | 13 | ||||
| Dyspepsia | 4 | 9 | ||||
| Constipation | 4 | 5 | ||||
| Flatulence | 2 | 4 | ||||
| Eructation | 1 | 2 | ||||
| Insomnia | 7 | 9 | ||||
| Confusion | 7 | 8 | ||||
| Depression | 4 | 6 | ||||
| Anxiety | 3 | 5 | ||||
| Hallucination | 3 | 4 | ||||
| Aggressive Reaction | 2 | 3 | ||||
| Urinary Tract Infection | 6 | 7 | ||||
| Rhinitis | 3 | 4 | ||||
| Body System/Adverse Event | ||||||
| 71 | 84 | |||||
| Nausea | 11 | 29 | ||||
| Vomiting | 2 | 17 | ||||
| Diarrhea | 4 | 7 | ||||
| Upper Abdominal Pain | 1 | 4 | ||||
| Fatigue | 3 | 4 | ||||
| Asthenia | 1 | 2 | ||||
| Anorexia | 3 | 6 | ||||
| Dehydration | 1 | 2 | ||||
| Tremor | 4 | 10 | ||||
| Dizziness | 1 | 6 | ||||
| Headache | 3 | 4 | ||||
| Somnolence | 3 | 4 | ||||
| Parkinson’s Disease (worsening) | 1 | 3 | ||||
| Parkinsonism | 1 | 2 | ||||
| Anxiety | 1 | 4 | ||||
| Insomnia | 2 | 3 |
What should I look out for while using Exelon?
Exelon (rivastigmine tartrate) is contraindicated in
patients with known hypersensitivity to rivastigmine, other carbamate
derivatives or other components of the formulation (see DESCRIPTION).
Exelon
(rivastigmine tartrate) use is
associated with significant gastrointestinal adverse reactions, including nausea
and vomiting, anorexia, and weight loss. For this reason, patients should always
be started at a dose of 1.5 mg BID and titrated to their maintenance dose. If
treatment is interrupted for longer than several days, treatment should be
reinitiated with the lowest daily dose (see DOSAGE AND ADMINISTRATION) 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).
Nausea and Vomiting:
In the
controlled clinical trials, 47% of the patients treated with an Exelon dose in
the therapeutic range of 6-12 mg/day (n=1189) developed nausea (compared with
12% in placebo). A total of 31% of Exelon-treated patients developed at least
one episode of vomiting
(compared with 6% for placebo).
The rate of vomiting was higher during the titration phase (24% vs. 3% for
placebo) than in the maintenance phase (14% vs. 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% vs. 9%
for placebo) than in the maintenance phase (17% vs. 4% for placebo).
Weight Loss:
In the
controlled trials, approximately 26% of women on high doses of Exelon (greater
than 9 mg/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:
Peptic Ulcers/Gastrointestinal Bleeding:
Exelon as a cholinesterase inhibitor, is likely to exaggerate
succinylcholine-type muscle relaxation during anesthesia.
Drugs that increase cholinergic activity may have vagotonic
effects on heart rate (e.g., bradycardia). The potential for this action may be
particularly important to patients with "sick sinus syndrome" or other
supraventricular cardiac conduction conditions. In clinical trials, Exelon was
not associated with any increased incidence of cardiovascular adverse events,
heart rate or blood pressure changes, or ECG abnormalities. Syncopal episodes
have been reported in 3% of patients receiving 6-12 mg/day of Exelon, compared
to 2% of placebo patients.
Although this was not observed in clinical trials of Exelon,
drugs that increase cholinergic activity may cause urinary obstruction.
Seizures:
Like other drugs that increase cholinergic activity, Exelon
should be used with care in patients with a history of asthma or obstructive
pulmonary disease.
What might happen if I take too much Exelon?
Because strategies for the management of overdose are continually
evolving, it is advisable to contact a Poison Control Center to determine the
latest recommendations for the management of an overdose of any drug.
As Exelon (rivastigmine tartrate) has a short
plasma half-life of about one hour and a moderate duration of
acetylcholinesterase inhibition of 8-10 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. Due to
the short half-life of Exelon, 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. In a documented case of a 46-mg overdose with
Exelon, the patient experienced vomiting, incontinence, hypertension,
psychomotor retardation, and loss of consciousness. The patient fully recovered
within 24 hours and conservative management was all that was required for
treatment.
How should I store and handle Exelon?
Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146 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 30………………………………………………... Bottles of 60..………………………………………………. Bottles of 60………………………………………………… 4.5 mg Capsule – red, “Exelon 4,5 mg” is printed in white on the body of the capsule. Bottles of 30……………………………………………….. Bottles of 60………………………………………………… REV: JUNE 2006 T2006-73 Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936©NovartisRepackaging and Relabeling by:Physicians Total Care, Inc. Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Pathological changes in dementia of the Alzheimer’s type and
dementia associated with Parkinson’s disease involve cholinergic neuronal
pathways that project from the basal forebrain to the cerebral cortex and
hippocampus. These pathways are thought to be intricately involved in memory,
attention, learning, and other cognitive processes. While the precise mechanism
of rivastigmine's action is unknown, it is postulated to exert its therapeutic
effect by enhancing cholinergic function. This is accomplished by increasing the
concentration of acetylcholine through reversible inhibition of its hydrolysis
by cholinesterase. If this proposed mechanism is correct, Exelon's effect 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. After a 6-mg dose of rivastigmine,
anticholinesterase activity is present in CSF for about 10 hours, with a maximum
inhibition of about 60% 5 hours after dosing.
and 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.
The effectiveness of Exelon (rivastigmine
tartrate) as a treatment for Alzheimer's disease is demonstrated by the results
of 2 randomized, double-blind, placebo-controlled clinical investigations in
patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV
criteria, Mini-Mental State Examination (MMSE) greater than or equal to 10 and less than or equal to 26, and the Global
Deterioration Scale (GDS)]. The mean age of patients participating in Exelon
trials was 73 years with a range of 41-95. Approximately 59% of patients were
women and 41% were men. The racial distribution was Caucasian 87%, Black 4% and
other races 9%.
Study Outcome Measures
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 6-12 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 3-8 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 three 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.
In a study of 26 weeks duration, 699 patients were randomized to
either a dose range of 1-4 mg or 6-12 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.
Effects on the ADAS-cog:
Figure 1: Time-course of the Change from
Baseline in ADAS-cog Score for Patients Completing 26 Weeks of
Treatment
Figure 2 illustrates the cumulative percentages of patients from each
of the three 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%, 1-4 mg 85%, and 6-12 mg 65%.
Effects on the CIBIC-Plus:
Figure 3: Frequency Distribution of CIBIC-Plus
Scores at Week 26
In a second study of 26 weeks duration, 725 patients were
randomized to either a dose range of 1-4 mg or 6-12 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.
Effects on the ADAS-cog:
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 three 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 6-12 mg/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%, 1-4 mg 86%, and 6-12 mg 67%.
Effects on the CIBIC-Plus:
Figure 6: Frequency Distribution of CIBIC-Plus
Scores at Week 26
In a study of 26 weeks duration, 702 patients were randomized to
doses of 3, 6, or 9 mg/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/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/day and 6 mg/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.
The effectiveness of Exelon as a treatment for dementia
associated with Parkinson’s disease is demonstrated by the results of one
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 greater than or equal to 10 and less than or equal to 24 at entry. The mean age of patients
participating in this trial was 72.7 years with a range of 50–91. 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%.
Study Outcome Measures
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."
Study Results
In this study, 541 patients were randomized to a dose range of 3–12 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.
Effects on the ADAS-cog:
Figure 7:Time Course of the Change from Baseline in
ADAS-cog Score for Patients Completing 24 Weeks of Treatment
Effects on the ADCS-CGIC:
Figure 8:Distribution of ADCS-CGIC Scores for
Patients Completing 24 Weeks of Treatment
Age, Gender and Race
Patients’ age, gender, or race did not predict clinical outcome of Exelon
treatment.
Rivastigmine is well absorbed with absolute bioavailability of
about 40% (3-mg dose). It shows linear pharmacokinetics up to 3 mg BID but is
non-linear at higher doses. Doubling the dose from 3 to 6 mg BID 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:
Distribution:
Rivastigmine is about 40% bound to plasma proteins at concentrations of
1-400 ng/mL, which cover the therapeutic concentration range. Rivastigmine
distributes equally between blood and plasma with a blood-to-plasma partition
ratio of 0.9 at concentrations ranging from 1-400 ng/mL.
Metabolism:
Elimination:
Hepatic Disease:
Renal Disease:
Age:
Gender and Race:
Nicotine Use:
Effect of Exelon on the Metabolism of
Other Drugs:
No pharmacokinetic interaction was observed between rivastigmine and
digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The
elevation of prothrombin time induced by warfarin is not affected by
administration of Exelon.
Effect of Other Drugs on the Metabolism of
Exelon:
Population PK analysis with a database of 625 patients showed that the
pharmacokinetics of rivastigmine were not influenced by commonly prescribed
medications such as antacids (n=77), antihypertensives (n=72), ß-blockers
(n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal
antiinflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177),
antianginals (n=35), and antihistamines (n=15). In addition, in clinical trials,
no increased risk of clinically relevant untoward effects was observed in
patients treated concomitantly with Exelon and these agents.
Non-Clinical Toxicology
Exelon (rivastigmine tartrate) is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation (see DESCRIPTION).Exelon
(rivastigmine tartrate) use is associated with significant gastrointestinal adverse reactions, including nausea and vomiting, anorexia, and weight loss. For this reason, patients should always be started at a dose of 1.5 mg BID and titrated to their maintenance dose. If treatment is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose (see DOSAGE AND ADMINISTRATION) 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).
Nausea and Vomiting:
In the controlled clinical trials, 47% of the patients treated with an Exelon dose in the therapeutic range of 6-12 mg/day (n=1189) developed nausea (compared with 12% in placebo). A total of 31% of Exelon-treated patients developed at least one episode of vomiting
(compared with 6% for placebo). The rate of vomiting was higher during the titration phase (24% vs. 3% for placebo) than in the maintenance phase (14% vs. 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% vs. 9% for placebo) than in the maintenance phase (17% vs. 4% for placebo).
Weight Loss:
In the controlled trials, approximately 26% of women on high doses of Exelon (greater than 9 mg/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:
Peptic Ulcers/Gastrointestinal Bleeding:
Exelon as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Drugs that increase cholinergic activity may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions. In clinical trials, Exelon was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or ECG abnormalities. Syncopal episodes have been reported in 3% of patients receiving 6-12 mg/day of Exelon, compared to 2% of placebo patients.
Although this was not observed in clinical trials of Exelon, drugs that increase cholinergic activity may cause urinary obstruction.
Seizures:
Like other drugs that increase cholinergic activity, Exelon should be used with care in patients with a history of asthma or obstructive pulmonary disease.
Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of ursodiol by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids and may be expected to interfere with ursodiol in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodiol.
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.
Caregivers should be instructed in the correct procedure for administering Exelon (rivastigmine tartrate) 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.
Caregivers and patients should be advised that like other cholinomimetics, Exelon may exacerbate or induce extrapyramidal symptoms. Worsening in patients with Parkinson’s disease, including an increased incidence or intensity of tremor, has been observed.
Effect of Exelon on the Metabolism of Other Drugs:
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon.
Effect of Other Drugs on the Metabolism of Exelon:
Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), ß-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal antiinflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15).
Use with Anticholinergics:
Use with Cholinomimetics and Other Cholinesterase Inhibitors:
In carcinogenicity studies conducted at dose levels up to 1.1 mg-base/kg/day in rats and 1.6 mg-base/kg/day in mice, rivastigmine was not carcinogenic. These dose levels are approximately 0.9 times and 0.7 times the maximum recommended human daily dose of 12 mg/day on a mg/m basis.
Rivastigmine was clastogenic in two in vitro assays in the presence, but not the absence, of metabolic activation. It caused structural chromosomal aberrations in V79 Chinese hamster lung cells and both structural and numerical (polyploidy) chromosomal aberrations in human peripheral blood lymphocytes. Rivastigmine was not genotoxic in three in vitro assays: the Ames test, the unscheduled DNA synthesis (UDS) test in rat hepatocytes (a test for induction of DNA repair synthesis), and the HGPRT test in V79 Chinese hamster cells. Rivastigmine was not clastogenic in the in vivo mouse micronucleus test.
Rivastigmine had no effect on fertility or reproductive performance in the rat at dose levels up to 1.1 mg-base/kg/day. This dose is approximately 0.9 times the maximum recommended human daily dose of 12 mg/day on a mg/m basis.
Pregnancy Category B:
It is not known whether rivastigmine is excreted in human breast milk. Exelon has no indication for use in nursing mothers.
There are no adequate and well-controlled trials documenting the safety and efficacy of Exelon in any illness occurring in children.
The rate of discontinuation due to adverse events in controlled clinical trials of Exelon (rivastigmine tartrate) was 15% for patients receiving 6-12 mg/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 events 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.
The most common adverse events, 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.
Exelon use is associated with significant nausea, vomiting, and weight loss (see WARNINGS).
Table 2 lists treatment-emergent signs and symptoms that were reported 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 6-12 mg/day than for those treated with placebo. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
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 events in the controlled studies. Nausea, vomiting and weight loss were more frequent in women than men.
Other adverse events observed at a rate of 2% or more on Exelon 6-12 mg/day but at a greater or equal rate on placebo were chest pain, peripheral edema, vertigo, back pain, arthralgia, pain, bone fracture, agitation, nervousness, delusion, paranoid reaction, upper respiratory tract infection, infection (general), coughing, pharyngitis, bronchitis, rash (general), urinary incontinence.
The rate of discontinuation due to adverse events in the single controlled trial of Exelon (rivastigmine tartrate) was 18.2% for patients receiving 3-12 mg/day compared to 11.2% for patients on placebo during the 24-week study.
The most frequent adverse events 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 vs. 0.6% placebo), vomiting (1.9% Exelon vs. 0.6% placebo), and tremor (1.7% Exelon vs. 0.0% placebo).
The most common adverse events, 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.
Table 3 lists treatment-emergent signs and symptoms that were reported 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 3-12 mg/day than for those treated with placebo. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
In general, adverse reactions were less frequent later in the course of treatment.
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 10-12 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.
Treatment-emergent signs and symptoms that occurred during 8 controlled clinical trials and 9 open-label trials in North America, Western Europe, Australia, South Africa, and Japan were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified WHO dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 5,297 patients from these trials who experienced that event while receiving Exelon. All adverse events occurring in at least 6 patients (approximately 0.1%) are included, except for those already listed elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused. Events are classified by body system and listed using the following definitions: frequent adverse events – those occurring in at least 1/100 patients; infrequent adverse events – those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to Exelon treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Autonomic Nervous System:
Infrequent:
Body as a Whole:
Frequent:
Infrequent:
Cardiovascular System:
Frequent:
Central and Peripheral Nervous System:
Frequent:
Infrequent:
Endocrine System:
Infrequent:
Gastrointestinal System:
Frequent:
Infrequent:
Hearing and Vestibular Disorders:
Frequent:
Heart Rate and Rhythm Disorders:
Frequent:
Infrequent:
Liver and Biliary System Disorders:
Infrequent:
Metabolic and Nutritional Disorders:
Frequent:
Infrequent:
Musculoskeletal Disorders:
Frequent:
Infrequent:
Myo-, Endo-, Pericardial and Valve Disorders:
Frequent:
Platelet, Bleeding, and Clotting Disorders:
Frequent:
I
nfrequent:
Psychiatric Disorders:
Frequent:
Infrequent:
Red Blood Cell Disorders:
Frequent:
Infrequent:
Reproductive Disorders (Female and
Male):
Infrequent:
Resistance Mechanism Disorders:
Infrequent:
Respiratory System:
Infrequent:
Skin and Appendages:
Frequent:
Infrequent:
Special Senses:
Infrequent:
Urinary System Disorders:
Frequent:
Infrequent:
Vascular (extracardiac) Disorders:
Infrequent:
Vision Disorders:
Frequent:
Infrequent:
White Cell and Resistance Disorders:
Infrequent:
Exelon has been administered to 485 individuals during clinical trials worldwide. Of these, 413 patients have been treated for at least 3 months, 253 patients have been treated for at least 6 months, and 113 patients have been treated for 1 year.
Additional treatment-emergent adverse events in patients with Parkinson’s disease dementia occurring in at least 1 patient (approximately 0.3%) are listed below, excluding events that are already listed above for the dementia of the Alzheimer’s type or elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused. Events are classified by body system and listed using the following definitions: frequent adverse events – those occurring in at least 1/100 patients; infrequent adverse events – those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to Exelon treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Cardiovascular System:
Frequent:
Infrequent:
Central and Peripheral Nervous System:
Frequent:
Infrequent:
Endocrine System:
Infrequent:
Gastrointestinal System:
Frequent:
Infrequent:
Hearing and Vestibular Disorders:
Frequent:
Infrequent:
Heart Rate and Rhythm Disorders:
Infrequent:
Liver and Biliary System Disorders:
Infrequent:
Musculoskeletal Disorders:
Frequent:
Infrequent:
Psychiatric Disorders:
Frequent:
Infrequent:
Reproductive Disorders (Female and
Male):
Infrequent:
Respiratory System:
Frequent:
Infrequent:
Urinary System Disorders:
Infrequent:
Vascular (extracardiac) Disorders:
Infrequent:
Vision Disorders:
Infrequent:
Voluntary reports of adverse events temporally associated with Exelon that have been received since market introduction that are not listed above, and that may or may not be causally related to the drug include the following:
Skin and Appendages:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
Review
Read user comments about the side effects, benefits, and effectiveness of losartan oral.
Overall User Ratings
515Total User Reviews
User Reviews
Learn about
User Reviews
Professional
Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
Tips
Interactions
Interactions
A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).