Rivastigmine Tartrate

1 INDICATIONS AND USAGE Rivastigmine tartrate capsules are an acetylcholinesterase inhibitor indicated for treatment of: Mild-to-moderate dementia of the Alzheimer’s type (AD) (1.1) Mild-to-moderate dementia associated with Parkinson’s disease (PD) (1.2) 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 DOSAGE AND ADMINISTRATION Alzheimer’s Disease (2.1): Initial Dose: Initiate treatment with 1.5 mg twice a day. Dose Titration: After a minimum of 2 weeks, if tolerated, increase dose to 3 mg twice a day and further to 4.5 mg twice a day and 6 mg twice a day if tolerated with a minimum of 2 weeks at each dose Parkinson’s Disease Dementia (PDD) (2.2): Initial Dose: Initiate treatment with 1.5 mg twice a day. Dose Titration: After a minimum of 4 weeks, if tolerated, increase dose to 3 mg twice a day and further to 4.5 mg twice a day and 6 mg twice a day if tolerated with a minimum of 4 weeks at each dose. Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening (2.1, 2.2). Rivastigmine tartrate oral solution and Rivastigmine tartrate capsules may be interchanged at equal doses (2.5) 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.

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)] Most common adverse reactions (greater than 5% and 2 times greater than placebo): nausea, vomiting, anorexia, dyspepsia, and asthenia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 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 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. Table 1: Most Frequent Adverse Reactions Leading to Withdrawal from Clinical Trials During Titration and Maintenance in Patients Receiving 6 mg to 12 mg per day Rivastigmine Tartrate Using a Forced-Dose Titration Study Phase Titration Maintenance Overall Rivastigmine Tartrate Placebo Rivastigmine Tartrate Placebo Rivastigmine Tartrate Placebo ≥6 to 12 mg/day ≥6 to 12 mg/day ≥6 to 12 mg/day (n=1,189) (n=868) (n=987) (n=788) (n=1,189) (n=868) Event/% Discontinuing Nausea 8 <1 1 <1 8 1 Vomiting 4 <1 1 <1 5 <1 Anorexia 2 0 1 <1 3 <1 Dizziness 2 <1 1 <1 2 <1 Adverse Reactions Observed at an Incidence of at Least 2% Table 2 lists adverse reactions that occurred in at least 2% of patients in placebo-controlled trials, and for which the rate of occurrence was greater for patients treated with 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. Table 2: Proportion of Adverse Reactions Observed with a Frequency of Greater Than or Equal to 2% and at a Rate Greater than Placebo in Clinical Trials Body System/Adverse Reaction Rivastigmine Tartrate (6 to 12 m g/day) (n=1,189) Placebo (n=868) Percent of Patients with any Adverse Event 92 79 Autonomic Nervous System Increased Sweating 4 1 Syncope 3 2 Body as a Whole Fatigue 9 5 Asthenia 6 2 Malaise 5 2 Decreased Weight ** 3 <1 Cardiovascular Disorders, General Hypertension 3 2 Central and Peripheral Nervous System Dizziness 21 11 Headache 17 12 Somnolence 5 3 Tremor 4 1 Gastrointestinal System Nausea* 47 12 Vomiting* 31 6 Diarrhea 19 11 Anorexia*** 17 3 Abdominal Pain 13 6 Dyspepsia 9 4 Psychiatric Disorders Insomnia 9 7 Confusion 8 7 Depression 6 4 Anxiety 5 3 Hallucination 4 3 Aggressive Reaction 3 2 Resistance Mechanism Disorders Urinary Tract Infection 7 6 * Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with a rivastigmine tartrate dose in the therapeutic range of 6 mg to 12 mg per day (n=1189) developed nausea (compared with 12% in placebo). A total of 31% of rivastigmine tartrate -treated patients developed at least 1 episode of vomiting (compared with 6% for placebo). The rate of vomiting was higher during the titration phase (24% versus 3% for placebo) than in the maintenance phase (14% versus 3% for placebo). The rates were higher in women than men. Five percent of patients discontinued for vomiting, compared to less than 1% for patients on placebo. Vomiting was severe in 2% of rivastigmine tartrate-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 (greater than 9 mg per day) had weight loss equal to or greater than 7% of their baseline weight compared to 6% in the placebo-treated patients. About 18% of the males in the high-dose group experienced a similar degree of weight loss compared to 4% in placebo-treated patients. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug. *** Anorexia: In the controlled clinical trials, of the patients treated with a rivastigmine tartrate dose of 6 mg to 12 mg per day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time course nor the severity of the anorexia is known. Mild-to-Moderate Parkinson’s Disease Dementia 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. Table 3: Proportion of Adverse Reactions Observed at a Frequency Greater Than or Equal to 2% and Occurring at Rate Greater than Placebo in Clinical Trials Active- Controlled Study Placebo-Controlled Study Body System/Adverse Reaction Rivastigmine Tartrate (3 to 12 mg/day) (n=294) Rivastigmine Tartrate (3 to 12 mg/day) (n=362) Placebo (n=179) Percent of Patients with any Adverse Reaction 88 84 71 Gastrointestinal Disorders Nausea 38 29 11 Vomiting 13 17 2 Diarrhea 8 7 4 Upper Abdominal Pain 4 4 1 Salivary hypersecretion 2 1 0 General Disorders and Administrative Site Conditions Fall 10 6 6 Fatigue 5 4 3 Asthenia 4 2 1 Metabolism and Nutritional Disorders Anorexia - 6 3 Decreased Appetite 5 8 5 Dehydration 1 2 1 Nervous System Disorders Tremor 23 10 4 Dizziness 8 6 1 Headache 4 4 3 Somnolence 6 4 3 Parkinson’s Disease (worsening) -* 3 1 Bradykinesia 3 3 2 Dyskinesia 3 1 1 Cogwheel rigidity 3 1 0 Hypokinesia 2 1 0 Parkinsonism - 2 1 Psychiatric Disorders Anxiety 4 4 1 Insomnia 2 3 2 Restlessness 1 3 2 Skin and Subcutaneous Tissue Disorders Increased Sweating 2 2 1 *Parkinson’s disease (worsening) in the active-controlled study was assessed by reported pre-identified adverse events (tremor, cogwheel rigidity, fall), each of them listed with corresponding frequencies. 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

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 14 C-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).