Rivastigmine Tartrate

1 INDICATIONS AND USAGE Rivastigmine tartrate capsule is 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 capsule should be taken with meals in divided doses in the morning and evening (2.1 , 2.2) . 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.

5 WARNINGS AND PRECAUTIONS Gastrointestinal 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) Discontinue 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 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 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 Rivasti…

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

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 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.

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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 ≥ 6 to 12mg/day (n=1,189) Placebo (n=868) Rivastigmine Tartrate ≥6 to 12mg/day (n=987) Placebo (n=788) Rivastigmine Tartrate ≥6 to 12 mg/day (n=1,189) Placebo (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 1…