1.1 Alzheimer’s Disease

Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia of the Alzheimer's type (AD).

1.2 Parkinson’s Disease Dementia

Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PD).

2.1 Dosing in Alzheimer's Disease

Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening.

The recommended dosage of rivastigmine tartrate capsules in Alzheimer’s disease (AD) 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 rivastigmine tartrate capsules.

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).

2.2 Dosing in Parkinson's Disease Dementia

Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening.

The dosage of rivastigmine tartrate capsules 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 rivastigmine tartrate capsules.

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).

2.3 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 rivastigmine tartrate capsules. 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)].

2.4 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.

2.5 Important Administration Instructions

Rivastigmine tartrate oral solution and rivastigmine tartrate capsules may be interchanged at equal doses.

3.1 Rivastigmine Tartrate Capsules

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 – pale yellow opaque / pale yellow opaque size “2” hard gelatin capsules radially imprinted with “B” on cap and “793” on body with black ink, filled with white to off-white free flowing powder.

3 mg capsule – orange opaque / orange opaque size “2” hard gelatin capsules radially imprinted with “B” on cap and “794” on body with black ink, filled with white to off-white free flowing powder.

4.5 mg capsule – coral red opaque / coral red opaque size “2” hard gelatin capsules radially imprinted with “B” on cap and “795” on body with black ink, filled with white to off-white free flowing powder.

6 mg capsule – orange opaque / coral red opaque size “2” hard gelatin capsules radially imprinted with “B” on cap and “796” on body with black ink, filled with white to off-white free flowing powder.

5.1 Gastrointestinal Adverse Reactions

Rivastigmine tartrate 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.

5.2 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 rivastigmine tartrate 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.

5.3 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 rivastigmine tartrate 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 rivastigmine tartrate capsules 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 rivastigmine tartrate, 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.

5.4 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 rivastigmine tartrate capsules, routinely evaluate the patient’s ability to continue driving or operating machinery.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Rivastigmine tartrate 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 rivastigmine tartrate’s cholinergic effects. These include nausea, vomiting, anorexia, dyspepsia, and asthenia.

Gastrointestinal Adverse Reactions

Rivastigmine tartrate 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 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 rivastigmine tartrate 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.

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 rivastigmine tartrate 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.

Mild-to-Moderate Parkinson’s Disease Dementia

Rivastigmine tartrate 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 rivastigmine tartrate’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 rivastigmine tartrate 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 rivastigmine tartrate and more frequent than those receiving placebo, were nausea (3.6% rivastigmine tartrate versus 0.6% placebo), vomiting (1.9% rivastigmine tartrate versus 0.6% placebo), and tremor (1.7% rivastigmine tartrate versus 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 rivastigmine tartrate 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of rivastigmine tartrate capsules. 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 Disorder: seizure

Psychiatric Disorders: Aggression, nightmares

Skin and Subcutaneous Tissue Disorders: Allergic dermatitis, application site hypersensitivity (patch), blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria

7.1 Metoclopramide

Due to the risk of additive extrapyramidal adverse reactions, the concomitant use of metoclopramide and rivastigmine tartrate is not recommended.

7.2 Cholinomimetic and Anticholinergic Medications

Rivastigmine tartrate 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 rivastigmine tartrate with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see Warnings and Precautions ( 5.3)].

7.3 Beta-blockers

Additive bradycardic effects resulting in syncope may occur when rivastigmine tartrate is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use of rivastigmine tartrate with beta-blockers is not recommended.

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risks associated with the use of rivastigmine tartrate in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses 2 to 4 times the maximum recommended human dose (MRHD) (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2) basis.

8.2 Lactation

Risk Summary

There are no data on the presence of rivastigmine in human milk, the effects on the breastfed infant, or the effects of rivastigmine on milk production. 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.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rivastigmine tartrate and any potential adverse effects on the breastfed infant from rivastigmine tartrate or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. The use of rivastigmine tartrate in pediatric patients (below 18 years of age) is not recommended.

8.5 Geriatric Use

Of the total number of patients in clinical studies of rivastigmine tartrate, 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.

8.6 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)].

8.7 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 rivastigmine tartrate in patients with severe hepatic impairment.

8.8 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)].

12.1 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.

12.2 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.

12.3 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 area under the curve (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 rivastigmine tartrate with food delays absorption (T max) by 90 minutes lowers C max 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 (V D) 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 greater than or equal to 60 mL/min); CL/F=1.7 L/min and 4.8 L/min, respectively. In patients with severe renal impairment (n=8, GFR less than 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR greater than or equal to 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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In oral carcinogenicity studies conducted at doses up to 1.1 mg/kg/day in rats and 1.6 mg/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 an mg/m 2 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/kg/day, a dose less than the MRHD on an mg/m 2 basis.