ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following adverse reactions are described below and elsewhere in the labeling: Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]. Allergic Dermatitis [see Warnings and Precautions (5.2)]. Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions (5.3)]. Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]. Allergic Dermatitis [see Warnings and Precautions (5.2)]. Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions (5.3)]. Most common adverse reactions (greater than 5% and times greater than placebo): nausea, vomiting, anorexia, dyspepsia, and asthenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 capsules have been administered to over 5,297 individuals during clinical trials worldwide. Of these, 4,326 patients have been treated for at least months, 3,407 patients have been treated for at least months, 2,150 patients have been treated for year, 1,250 patients have been treated for years, and 168 patients have been treated for over 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 months, 2,328 patients treated for months, 1,378 patients treated for year, 917 patients treated for years, and 129 patients treated for over years. Mild-to-Moderate Alzheimers DiseaseMost Common Adverse ReactionsThe most common adverse reactions, defined as those occurring at frequency of at least 5% and twice the placebo rate, are largely predicted by rivastigmine tartrate capsules cholinergic effects. These include nausea, vomiting, anorexia, dyspepsia, and asthenia. Gastrointestinal Adverse ReactionsRivastigmine tartrate capsule use is associated with significant nausea, vomiting, and weight loss [see Warnings and Precautions (5.1)]. Discontinuation RatesThe rate of discontinuation due to adverse events in controlled clinical trials of rivastigmine tartrate capsules was 15% for patients receiving mg to 12 mg per day compared to 5% for patients on placebo during forced weekly dose titration. While on maintenance dose, the rates were 6% for patients on rivastigmine tartrate capsules compared to 4% for those on placebo. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1. Table 1: Most Frequent Adverse Reactions Leading to Withdrawal from Clinical Trials During Titration and Maintenance in Patients Receiving mg to 12 mg per day Rivastigmine Tartrate Capsules Using Forced-Dose TitrationStudy Phase TitrationMaintenanceOverallRivastigmineTartrate Capsules>=6 to 12 mg/day(n=1,189) Placebo(n=868)RivastigmineTartrate Capsules >=6 to 12 mg/day(n=987) Placebo(n=788)RivastigmineTartrate Capsules>=6 to 12 mg/day(n=1,189) Placebo(n=868)Event/% Discontinuing Nausea 8<11<181Vomiting 4<11<15<1Anorexia 201<13<1Dizziness 2<11<12<1Adverse Reactions Observed at an Incidence of at Least 2%Table 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 capsule doses of mg to 12 mg per day than for those treated with placebo. In general, adverse reactions were less frequent later in the course of treatment. No systematic effect of race or age could be determined from the incidence of adverse reactions in the controlled studies. Nausea, vomiting and weight loss were more frequent in women than men. Table 2: Proportion of Adverse Reactions Observed with Frequency of Greater Than or Equal to 2% and at Rate Greater than Placebo in Clinical Trials Body System/Adverse Reaction Rivastigmine Tartrate Capsules(6 to 12 mg/day)(n=1,189) Placebo(n=868)Percent of Patients with any Adverse Event 9279Autonomic Nervous System Increased Sweating 41 Syncope 32Body as Whole Fatigue 95 Asthenia 62 Malaise 52 Decreased Weight 3<1Cardiovascular Disorders, General Hypertension 32Central and Peripheral Nervous System Dizziness 2111 Headache 1712 Somnolence 53 Tremor 41Gastrointestinal System Nausea 4712 Vomiting 316 Diarrhea 1911 Anorexia 173 Abdominal Pain 136 Dyspepsia 94Psychiatric Disorders Insomnia 97 Confusion 87 Depression 64 Anxiety 53 Hallucination 43 Aggressive Reaction 32Resistance Mechanism Disorders Urinary Tract Infection 76Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an rivastigmine tartrate capsule dose in the therapeutic range of mg to 12 mg per day (n=1189) developed nausea (compared with 12% in placebo). total of 31% of rivastigmine tartrate capsule-treated patients developed at least episode of vomiting (compared with 6% for placebo). The rate of vomiting was higher during the titration phase (24% versus 3% for placebo) than in the maintenance phase (14% versus 3% for placebo). The rates were higher in women than men. Five percent of patients discontinued for vomiting, compared to less than 1% for patients on placebo. Vomiting was severe in 2% of rivastigmine tartrate capsule-treated patients and was rated as mild or moderate each in 14% of patients. The rate of nausea was higher during the titration phase (43% versus 9% for placebo) than in the maintenance phase (17% versus 4% for placebo). Weight Decreased: In the controlled trials, approximately 26% of women on high doses of rivastigmine tartrate capsules (greater than mg per day) had weight loss equal to or greater than 7% of their baseline weight compared to 6% in the placebo-treated patients. About 18% of the males in the high-dose group experienced similar degree of weight loss compared to 4% in placebo-treated patients. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug. Anorexia: In the controlled clinical trials, of the patients treated with an rivastigmine tartrate capsule dose of mg to 12 mg per day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time course nor the severity of the anorexia is known.Mild-to-Moderate Parkinsons Disease DementiaRivastigmine tartrate capsules have been administered to 779 individuals during clinical trials worldwide. Of these, 663 patients have been treated for at least months, 476 patients have been treated for at least months, and 313 patients have been treated for year. Most Common Adverse ReactionsThe most common adverse reactions, defined as those occurring at frequency of at least 5% and twice the placebo rate, are largely predicted by rivastigmine tartrate capsules cholinergic effects. These include nausea, vomiting, tremor, anorexia, and dizziness. Discontinuation RatesThe rate of discontinuation due to adverse events in the single placebo-controlled trial of rivastigmine tartrate capsules were 18% for patients receiving 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 capsules and more frequent than those receiving placebo, were nausea (3.6% rivastigmine tartrate capsules versus 0.6% placebo), vomiting (1.9% rivastigmine tartrate capsules versus 0.6% placebo), and tremor (1.7% rivastigmine tartrate capsules versus 0.0% placebo). Adverse Reactions Observed at an Incidence of at Least 2% Table lists adverse reactions that occurred in at least 2% of patients in single placebo-controlled trial and during the first 24 weeks of 76-week open-label active-controlled trial for which the rate of occurrence was greater for patients treated with rivastigmine tartrate capsule doses of mg to 12 mg per day than for those treated with placebo in the placebo-controlled trial. In general, adverse reactions were less frequent later in the course of treatment. Table 3: Proportion of Adverse Reactions Observed at Frequency Greater Than or Equal to 2% and Occurring at Rate Greater than Placebo in Clinical Trials Active-Controlled StudyPlacebo-Controlled Study Body System/Adverse Reaction Rivastigmine TartrateCapsules(3 to 12 mg/day)(n=294)Rivastigmine Tartrate Capsules(3 to 12 mg/day)(n=362) Placebo (n=179) Percent of Patients with any Adverse Event888471 Gastrointestinal Disorders Nausea 382911 Vomiting 13172 Diarrhea 874 Upper Abdominal Pain 441 Salivary hypersecretion210General Disorders and Administrative Site Conditions Fall1066 Fatigue543 Asthenia 421Metabolism and Nutritional Disorders Anorexia-63 Decreased Appetite585 Dehydration121Nervous System Disorders Tremor23104 Dizziness861 Headache443 Somnolence643 Parkinsons Disease (worsening)-31 Bradykinesia332 Dyskinesia311 Cogwheel rigidity310 Hypokinesia210 Parkinsonism -21Psychiatric Disorders Anxiety441 Insomnia232 Restlessness132Skin and Subcutaneous Tissue Disorders Increased Sweating221Parkinsons disease (worsening) in the active-controlled study was assessed by reported pre-identified adverse events (tremor, cogwheel rigidity, fall), each of them listed with corresponding frequencies.. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Cardiac Disorders: Tachycardia.Hepatobiliary Disorders: Abnormal liver function tests, hepatitis. Nervous System Disorders: seizure.Psychiatric Disorders: Aggression, nightmares.Skin and Subcutaneous Tissue Disorders: Allergic dermatitis, application site hypersensitivity (patch), blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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/m2 basis. MutagenesisRivastigmine 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 FertilityRivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg/kg/day, dose less than the MRHD on mg/m2 basis.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 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 6-mg dose of rivastigmine, anticholinesterase activity is present in cerebrospinal fluid (CSF) for about 10 hours, with maximum inhibition of about 60% 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 mg twice day but is nonlinear at higher doses. Doubling the dose from mg to mg twice day results in 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. AbsorptionRivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately hour. Absolute bioavailability after 3-mg dose is about 36%. Administration of rivastigmine tartrate capsules with food delays absorption (Tmax) by 90 minutes lowers Cmax by approximately 30% and increases AUC by approximately 30%. DistributionRivastigmine 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 (VD) in the range of 1.8 to 2.7 L/kg. MetabolismRivastigmine 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.EliminationThe major pathway of elimination is via the kidneys. Following administration of 14C-rivastigmine to 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 mg twice day. AgeFollowing 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 RacePopulation pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, Asian, and 12 Other) affected clearance of the drug. Body Weight relationship between drug exposure at steady-state (rivastigmine and metabolite NULLP226-90) and body weight was observed in Alzheimers dementia patients. Rivastigmine exposure is higher in subjects with low body weight. Compared to patient with body weight of 65 kg, the rivastigmine steady-state concentrations in patient with body weight of 35 kg would be approximately doubled, while for patient with body weight of 100 kg the concentrations would be approximately halved.Renal ImpairmentFollowing 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 higher clearance of rivastigmine than moderately impaired patients. Hepatic ImpairmentFollowing 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 day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score to 6), and moderate (n=3, Child-Pugh score to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10).SmokingFollowing 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 StudiesEffect of Rivastigmine on the Metabolism of Other DrugsRivastigmine 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 RivastigmineDrugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Population pharmacokinetic analysis with 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).

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. Mild-to-Moderate Alzheimers Disease The effectiveness of rivastigmine tartrate capsules as treatment for Alzheimers disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations (Study and Study 2) in patients with Alzheimers 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 rivastigmine tartrate capsules trials was 73 years with range of 41 to 95. Approximately 59% of patients were women and 41% were men. The racial distribution was Caucasian 87%, Black 4%, and other races 9%. In each study, the effectiveness of rivastigmine tartrate capsules was evaluated using dual outcome assessment strategy. The ability of rivastigmine tartrate capsules to improve cognitive performance was assessed with the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog), multi-text instrument that has been extensively validated in longitudinal cohorts of Alzheimers 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 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 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 range from to 61. Experience gained in longitudinal studies of ambulatory patients with mild-to-moderate Alzheimers disease suggests that they gain to 12 units 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 rivastigmine tartrate capsule trials was approximately to units per year. The ability of rivastigmine tartrate capsules to produce an overall clinical effect was assessed using Clinicians Interview-Based Impression of Change (CIBIC) that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not single instrument and is not standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used variety of CIBIC formats, each different in terms of depth and structure. As such, results from 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 rivastigmine tartrate capsule trials was structured instrument based on comprehensive evaluation at baseline and subsequent time-points of domains: patient cognition, behavior and functioning, including assessment of activities of daily living. It represents the assessment of 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 7-point categorical rating, ranging from score of 1, indicating markedly improved, to score of 4, indicating no change to score of 7, indicating marked worsening. The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers or other global methods. U.S. 26-Week Study of Rivastigmine Tartrate Capsules in Mild-to-Moderate Alzheimers Disease (Study 1)In study of 26 weeks duration, 699 patients were randomized to either dose range of mg to mg or mg to 12 mg of rivastigmine tartrate capsules per day or to placebo, each given in divided doses. The 26-week study was divided into 12-week forced-dose titration phase and 14-week maintenance phase. The patients in the active treatment arms of the study were maintained at their highest tolerated dose within the respective range. Figure illustrates the time course for the change from baseline in ADAS-cog scores for all dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the rivastigmine tartrate capsule-treated patients compared to the patients on placebo were 1.9 and 4.9 units for the mg to mg and mg to 12 mg treatments, respectively. Both treatments were statistically significantly superior to placebo and the mg to 12 mg per day range was significantly superior to the mg to mg per day range. Figure 1: Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment in Study Figure illustrates the cumulative percentages of patients from each of the 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 rivastigmine tartrate capsules and placebo have wide range of responses, but that the rivastigmine tartrate capsules groups are more likely to show the greater improvements. 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%, mg to mg 85%, and mg to 12 mg 65%. Figure is histogram of the frequency distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 26 weeks of treatment. The mean rivastigmine tartrate capsule-placebo differences for these groups of patients in the mean rating of change from baseline were 0.32 units and 0.35 units for mg to mg and mg to 12 mg of rivastigmine tartrate capsules, respectively. The mean ratings for the mg to 12 mg per day and mg to mg per day groups were statistically significantly superior to placebo. The differences between the mg to 12 mg per day and the mg to mg per day groups were statistically significant. Figure 3: Frequency Distribution of CIBIC-Plus Scores at Week 26 in Study Global 26-Week Study in Mild-to-Moderate Alzheimers Disease (Study 2)In second study of 26 weeks duration, 725 patients were randomized to either dose range of mg to mg or mg to 12 mg of rivastigmine tartrate capsules per day or to placebo, each given in divided doses. The 26-week study was divided into 12-week forced-dose titration phase and 14-week maintenance phase. The patients in the active treatment arms of the study were maintained at their highest tolerated dose within the respective range. Figure illustrates the time course for the change from baseline in ADAS-cog scores for all dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the rivastigmine tartrate capsule-treated patients compared to the patients on placebo were 0.2 and 2.6 units for the mg to mg and mg to 12 mg treatments, respectively. The mg to 12 mg per day group was statistically significantly superior to placebo, as well as to the mg to mg per day group. The difference between the mg to mg per day group and placebo was not statistically significant. Figure 4: Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment Figure illustrates the cumulative percentages of patients from each of the 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 rivastigmine tartrate capsules and placebo have wide range of responses, but that the mg to 12 mg per day rivastigmine tartrate capsules 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%, mg to mg 86%, and mg to 12 mg 67%. Figure is histogram of the frequency distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 26 weeks of treatment. The mean rivastigmine tartrate capsule-placebo differences for these groups of patients for the mean rating of change from baseline were 0.14 units and 0.41 units for mg to mg and mg to 12 mg of rivastigmine tartrate capsules, respectively. The mean ratings for the mg to 12 mg per day group were statistically significantly superior to placebo. The comparison of the mean ratings for the mg to mg per day group and placebo group was not statistically significant. Figure 6: Frequency Distribution of CIBIC-Plus Scores at Week 26 in Study U.S. Fixed-Dose Study in Mild-to-Moderate Alzheimers Disease (Study 3)In study of 26 weeks duration, 702 patients were randomized to doses of mg, mg, or mg per day of rivastigmine tartrate capsules or to placebo, each given in divided doses. The fixed-dose study design, which included 12-week forced-dose titration phase and 14-week maintenance phase, led to high dropout rate in the mg per day group because of poor tolerability. At 26 weeks of treatment, significant differences were observed for the ADAS-cog mean change from baseline for the mg per day and mg per day groups, compared to placebo. No significant differences were observed between any of the rivastigmine tartrate capsule-dose groups and placebo for the analysis of the CIBIC-Plus mean rating of change. Although no significant differences were observed between rivastigmine tartrate capsule treatment groups, there was trend toward numerical superiority with higher doses. Mild-to-Moderate Parkinsons Disease DementiaInternational 24-Week Study (Study 4)The effectiveness of rivastigmine tartrate capsules as treatment for dementia associated with Parkinsons disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigation in patients with mild-to-moderate dementia, with onset at least years after the initial diagnosis of idiopathic Parkinsons disease. The diagnosis of idiopathic Parkinsons disease was based on the United Kingdom Parkinsons 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 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 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 range of 50 to 91 years. Approximately, 35.1% of patients were women and 64.9% of patients were men. The racial distribution was 99.6% Caucasian and other races 0.4%. This study used dual outcome assessment strategy to evaluate the effectiveness of rivastigmine tartrate capsules. The ability of rivastigmine tartrate capsules to improve cognitive performance was assessed with the ADAS-cog. The ability of rivastigmine tartrate capsules to produce an overall clinical effect was assessed using the Alzheimers Disease Cooperative Study Clinicians Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is more standardized form of CIBIC-Plus and is also scored as 7-point categorical rating, ranging from score of 1, indicating markedly improved, to score of 4, indicating no change to score of 7, indicating marked worsening. In this study, 541 patients were randomized to dose range of mg to 12 mg of rivastigmine tartrate capsules per day or to placebo in ratio of 2:1, given in divided doses. The 24-week study was divided into 16-week titration phase and an 8-week maintenance phase. The patients in the active treatment arm of the study were maintained at their highest tolerated dose within the specified dose range. Figure illustrates the time course for the change from baseline in ADAS-cog scores for both treatment groups over the 24-week study. At 24 weeks of treatment, the mean difference in the ADAS-cog change scores for the rivastigmine tartrate capsule-treated patients compared to the patients on placebo was 3.8 points. This treatment difference was statistically significant in favor of rivastigmine tartrate capsules when compared to placebo.Figure 7: Time Course of the Change from Baseline in ADAS-cog Score for Patients Completing 24 Weeks of Treatment in Study Figure is histogram of the distribution of patients scores on the ADCS-CGIC (Alzheimers Disease Cooperative Study Clinicians Global Impression of Change) at 24 weeks. The mean difference in change scores between the rivastigmine tartrate capsules and placebo groups from baseline was 0.5 points. This difference was statistically significant in favor of rivastigmine tartrate capsule treatment.Figure 8: Distribution of ADCS-CGIC Scores for Patients Completing 24 Weeks of Treatment in Study Patients age, gender, or race did not predict clinical outcome of rivastigmine tartrate capsule treatment. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. 1. 1.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Rivastigmine tartrate capsules are contraindicated in patients with: oknown hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation [see Description (11) ]. oa previous history of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing [see Warnings and Precautions (5.2)]. Isolated cases of generalized skin reactions have been described in postmarketing experience [see Adverse Reactions (6.2)]. oknown hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation [see Description (11) ]. oa previous history of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing [see Warnings and Precautions (5.2)]. oKnown hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation. (4) oHistory of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing. (4, 5.2) oKnown hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation. (4) oHistory of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing. (4, 5.2).

DESCRIPTION SECTION.


11 DESCRIPTION. Rivastigmine Tartrate Capsules USP are 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, USP is commonly referred to in the pharmacological literature as SDZ ENULL 713 or ENULL 713. It has molecular formula of C14H22N2O2 C4H6O6 (hydrogen tartrate salt-hta salt) and molecular weight of 400.43 (hta salt). Rivastigmine tartrate, USP is 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 37C in n-octanol/phosphate buffer solution pH is 3.0. Rivastigmine Tartrate Capsules USP contain rivastigmine tartrate USP, equivalent to 1.5 mg, mg, 4.5 mg, and mg of rivastigmine base for oral administration. Inactive ingredients are colloidal silicon dioxide, hypromellose, magnesium stearate, and microcrystalline cellulose. The capsule shell contains gelatin, titanium dioxide, and yellow iron oxide. The 1.5 mg capsule shell also contains red iron oxide. The 4.5 and mg capsule shell also contains red iron oxide and black iron oxide. The imprinting ink, common for all strengths, contains: black iron oxide, D&C yellow 10 aluminum lake, FD&C blue brilliant blue FCF aluminum lake, FD&C blue indigo carmine aluminum lake, FD&C red 40 allura red AC aluminum lake, shellac and may contain propylene glycol.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Alzheimers Disease (2.1):oInitial Dose: Initiate treatment with 1.5 mg twice day oDose Titration: After minimum of weeks, if tolerated, increase dose to mg twice day and further to 4.5 mg twice day and mg twice day if tolerated with minimum of weeks at each dose Parkinsons Disease Dementia (PDD) (2.2):oInitial Dose: Initiate treatment with 1.5 mg twice day oDose Titration: After minimum of weeks, if tolerated, increase dose to mg twice day and further to 4.5 mg twice day and mg twice day if tolerated with minimum of weeks at each dose Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening. (2.1, 2.2) oInitial Dose: Initiate treatment with 1.5 mg twice day oDose Titration: After minimum of weeks, if tolerated, increase dose to mg twice day and further to 4.5 mg twice day and mg twice day if tolerated with minimum of weeks at each dose oInitial Dose: Initiate treatment with 1.5 mg twice day oDose Titration: After minimum of weeks, if tolerated, increase dose to mg twice day and further to 4.5 mg twice day and mg twice day if tolerated with minimum of weeks at each dose 2.1 Dosing in Alzheimers 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 Alzheimers disease (AD) is mg to 12 mg per day, administered twice day (daily doses of mg to mg twice day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial. Initial DoseInitiate treatment with the 1.5 mg twice day with rivastigmine tartrate capsules. Dose TitrationAfter minimum of weeks and if well tolerated, increase the dose to mg twice day. Subsequent increases to 4.5 mg twice day and mg twice day should be attempted after minimum of weeks at the previous dose and if well tolerated. The maximum dose is mg twice day (12 mg per day). 2.2 Dosing in Parkinsons 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 Parkinsons disease is mg to 12 mg per day, administered twice day (daily doses of 1.5 mg to mg twice day). Initial DoseInitiate treatment with the 1.5 mg twice day with rivastigmine tartrate capsules. Dose TitrationAfter minimum of weeks and if well tolerated, increase the dose to mg twice day. Subsequent increases to 4.5 mg twice day and mg twice day should be attempted after minimum of weeks at the previous dose and if well tolerated. The maximum dose is mg twice 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 days or fewer, restart treatment with the same or lower dose of rivastigmine tartrate capsules. If dosing is interrupted for more than days, treatment should be restarted with 1.5 mg twice day and titrated as described above [see Warnings and Precautions (5.1)]. 2.4 Dosing in Specific Populations Dosing Modifications in Patients with Renal ImpairmentPatients with moderate and severe renal impairment may be able to only tolerate lower doses.Dosing Modifications in Patients with Hepatic ImpairmentPatients with mild (Child-Pugh score to 6) and moderate (Child-Pugh score 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 WeightCarefully 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.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Rivastigmine Tartrate Capsules USP, contain rivastigmine tartrate, USP equivalent to 1.5 mg, mg, 4.5 mg, or mg of rivastigmine base, are available as follows: 1.5 mg Hard gelatin capsules with orange opaque cap and body printed with WATSON over 3208 on both cap and body in black ink. mg Hard gelatin capsules with yellow opaque cap and body printed with WATSON over 3209 on both cap and body in black ink.4.5 mg Hard gelatin capsules with light brown opaque cap and body printed with WATSON over 3210 on both cap and body in black ink.6 mg Hard gelatin capsules with light brown opaque cap and orange opaque body printed with WATSON over 3211 on both cap and body in black ink.. oCapsules: 1.5 mg, mg, 4.5 mg, or mg (3) oCapsules: 1.5 mg, mg, 4.5 mg, or mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Concomitant use with metoclopramide, beta-blockers, or cholinomimetic and anticholinergic drugs is not recommended (7.1, 7.2, 7.3). 7.1 Metoclopramide. Due to the risk of additive extrapyramidal adverse reactions, the concomitant use of metoclopramide and rivastigmine is not recommended. 7.2 Cholinomimetic and Anticholinergic Medications Rivastigmine 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 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 is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use of rivastigmine with beta-blockers is not recommended.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Of the total number of patients in clinical studies of rivastigmine tartrate capsules, 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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Rivastigmine Tartrate Capsules USP equivalent to 1.5 mg, mg, 4.5 mg, or mg of rivastigmine base are available as follows:1.5 mg Hard gelatin capsules with orange opaque cap and body printed with WATSON over 3208 on both cap and body in black ink. Carton of 100 capsules (10 capsules each blister pack 10) NDC 0904-6587-61Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature]. Dispense in tight, light-resistant container as defined in the USP.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. Rivastigmine tartrate capsules are an acetylcholinesterase inhibitor indicated for treatment of: oMild-to-moderate dementia of the Alzheimers type (AD) (1.1) oMild-to-moderate dementia associated with Parkinsons disease (PD) (1.2) oMild-to-moderate dementia of the Alzheimers type (AD) (1.1) oMild-to-moderate dementia associated with Parkinsons disease (PD) (1.2) 1.1 Alzheimers Disease. Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia of the Alzheimers type (AD). 1.2 Parkinsons Disease Dementia. Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia associated with Parkinsons disease (PD).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Gastrointestinal Adverse ReactionsCaregivers should be advised of the high incidence of nausea and vomiting associated with the use of the drug along with the possibility of anorexia and weight loss. Caregivers should be encouraged to monitor for these adverse events and inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than several days, the next dose should not be administered until they have discussed this with the physician [see Warnings and Precautions (5.1)]. Skin ReactionsCaregivers and patients should be advised that allergic skin reactions have been reported in association with rivastigmine tartrate capsules regardless of formulation (capsules, oral solution or transdermal patch). In case of skin reaction while taking rivastigmine tartrate capsules, patients should consult with their physician immediately [see Warnings and Precautions (5.2)]. Concomitant Use of Drugs with Cholinergic ActionCaregivers and patients should be advised that cholinomimetics, including rivastigmine, may exacerbate or induce extrapyramidal symptoms. Worsening in patients with Parkinsons disease, including an increased incidence or intensity of tremor, has been observed [see Warnings and Precautions (5.3)].PregnancyAdvise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.Manufactured In India By:Cipla Ltd.Verna, Goa INDIA Distributed By:Actavis Pharma, Inc.Parsippany, NJ 07054 USADistributed By:MAJOR(R) PHARMACEUTICALS17177 Laurel Park Dr., Suite 233Livonia, MI 48152Rev. 3/2019.

MECHANISM OF ACTION SECTION.


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.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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/m2 basis. MutagenesisRivastigmine 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 FertilityRivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg/kg/day, dose less than the MRHD on mg/m2 basis.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Because strategies for the management of overdose are continually evolving, it is advisable to contact Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As rivastigmine has short plasma half-life of about hour and moderate duration of acetylcholinesterase inhibition of to 10 hours, it is recommended that in cases of asymptomatic overdoses, no further dose of rivastigmine tartrate capsules 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 possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when coadministered with quaternary anticholinergics such as glycopyrrolate. Additional symptoms associated with rivastigmine overdose are diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, confusional state, hyperhidrosis, hypertension, hallucinations and malaise. Due to the short half-life of rivastigmine, dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be clinically indicated in the event of an overdose. In overdoses accompanied by severe nausea and vomiting, the use of antiemetics should be considered. fatal outcome has been rarely reported with rivastigmine.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Package/Label Display Panel Rivastigmine Tartrate Capsules, USP1.5 mg100 Capsules. carton label.

PEDIATRIC USE SECTION.


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

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. After 6-mg dose of rivastigmine, anticholinesterase activity is present in cerebrospinal fluid (CSF) for about 10 hours, with maximum inhibition of about 60% hours after dosing. In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Rivastigmine shows linear pharmacokinetics up to mg twice day but is nonlinear at higher doses. Doubling the dose from mg to mg twice day results in 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. AbsorptionRivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately hour. Absolute bioavailability after 3-mg dose is about 36%. Administration of rivastigmine tartrate capsules with food delays absorption (Tmax) by 90 minutes lowers Cmax by approximately 30% and increases AUC by approximately 30%. DistributionRivastigmine 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 (VD) in the range of 1.8 to 2.7 L/kg. MetabolismRivastigmine 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.EliminationThe major pathway of elimination is via the kidneys. Following administration of 14C-rivastigmine to 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 mg twice day. AgeFollowing 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 RacePopulation pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, Asian, and 12 Other) affected clearance of the drug. Body Weight relationship between drug exposure at steady-state (rivastigmine and metabolite NULLP226-90) and body weight was observed in Alzheimers dementia patients. Rivastigmine exposure is higher in subjects with low body weight. Compared to patient with body weight of 65 kg, the rivastigmine steady-state concentrations in patient with body weight of 35 kg would be approximately doubled, while for patient with body weight of 100 kg the concentrations would be approximately halved.Renal ImpairmentFollowing 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 higher clearance of rivastigmine than moderately impaired patients. Hepatic ImpairmentFollowing 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 day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score to 6), and moderate (n=3, Child-Pugh score to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10).SmokingFollowing 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 StudiesEffect of Rivastigmine on the Metabolism of Other DrugsRivastigmine 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 RivastigmineDrugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Population pharmacokinetic analysis with 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).

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk Summary There are no adequate data on the developmental risks associated with the use of rivastigmine tartrate capsules in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses to 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.DataAnimal DataOral 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 and times, respectively, the MRHD of 12 mg per day on body surface area (mg/m2) basis.

SPL UNCLASSIFIED SECTION.


1.1 Alzheimers Disease. Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia of the Alzheimers type (AD).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary There are no adequate data on the developmental risks associated with the use of rivastigmine tartrate capsules in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses to 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.DataAnimal DataOral 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 and times, respectively, the MRHD of 12 mg per day on body surface area (mg/m2) basis.. 8.2 Lactation. Risk SummaryThere 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 times that in maternal plasma.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for rivastigmine tartrate capsule and any potential adverse effects on the breastfed infant from rivastigmine tartrate capsule or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established. The use of rivastigmine 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 capsules, 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 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)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. oGastrointestinal adverse reactions may include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. (5.1) oDiscontinue rivastigmine in case of disseminated allergic dermatitis, which may occur after oral or transdermal administration. (4, 5.2) In patients with suspected allergic contact dermatitis after transdermal rivastigmine use, switch to oral rivastigmine only after negative allergy testing. oGastrointestinal adverse reactions may include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. (5.1) oDiscontinue rivastigmine in case of disseminated allergic dermatitis, which may occur after oral or transdermal administration. (4, 5.2) In patients with suspected allergic contact dermatitis after transdermal rivastigmine use, switch to oral rivastigmine only after negative allergy testing. 5.1 Gastrointestinal Adverse Reactions. Rivastigmine tartrate capsules 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 dose of 1.5 mg twice day and titrated to their maintenance dose. If treatment is interrupted for longer than 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 4.5-mg dose after 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 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 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 EffectsExtrapyramidal 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 Parkinsons 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 manifestation of Alzheimers disease. Peptic Ulcers/Gastrointestinal BleedingCholinesterase 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 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 AnesthesiaRivastigmine, as cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Cardiac Conduction EffectsBecause 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 mg to 12 mg per day of rivastigmine tartrate capsules, compared to 2% of placebo patients. Genitourinary EffectsAlthough not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction. Pulmonary EffectsDrugs that increase cholinergic activity, including rivastigmine, should be used with care in patients with 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 the rivastigmine tartrate capsules, routinely evaluate the patients ability to continue driving or operating machinery.