Rivastigmine Tartrate

Dosage and Administration, Dosing in Specific Populations (2.2) 9/2013 Contraindications (4) 9/2013 Warnings and Precautions, Hypersensitivity Reactions of the Skin (5.2) 9/2013

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 & ADMINISTRATION Alzheimer’s Disease: Initiate treatment with 1.5 mg twice a day 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 (2.1) Parkinson’s Disease Dementia: Initiate treatment with 1.5 mg twice a day 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 (2.2) Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening. (2.1) Rivastigmine tartrate oral solution and Rivastigmine tartrate capsules may be interchanged at equal doses. (2.3) 2.1 Recommended Dosing Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening. Alzheimer’s Disease The dosage of Rivastigmine tartrate capsules shown to be effective in controlled clinical trials in Alzheimer’s disease 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). Parkinson’s Disease Dementia 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). 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)] . 2.2 Dosing in Specific Populations Dosing Modifications in Patients with Renal or Hepatic Impairment Pharmacokinetic studies of oral rivastigmine in patients with moderate to severe renal impairment (glomerular filtration rate [GFR] <50 mL/min) and mild to moderate hepatic impairment (Child-Pugh score 5 to 9) showed reduced clearance of the drug [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . Accordingly, such patients 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 Because rivastigmine blood levels vary with body weight [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)] , careful titration and monitoring should be performed in patients with low body weight. In patients with low body weight (less than 50 kg), monitor closely for toxicities (e.g., excessive nausea, vomiting), and consider reducing the dose if such toxicities develop. 2.3 Important Administration Instructions Rivastigmin …

3 DOSAGE FORMS AND STRENGTHS Capsules: 1.5 mg, 3 mg, 4.5 mg, or 6 mg ( 3.1 ) 3.1 Rivastigmine Tartrate Capsules Capsules, containing rivastigmine tartrate equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of rivastigmine base, are available as follows: Rivastigmine tartrate capsules USP, 1.5 mg are white to off-white powder filled in size ‘2’ hard gelatin capsules with light tan opaque color cap and light tan opaque color body, imprinted ‘RDY” on cap and ‘352’ on body with black ink. Rivastigmine tartrate capsules USP, 3 mg are white to off-white powder filled in size ‘2’ hard gelatin capsules with brown opaque color cap and brown opaque color body, imprinted ‘RDY’ on cap and ‘353’ on body with black ink. Rivastigmine tartrate capsules USP, 4.5 mg are white to off-white powder filled in size ‘2’ hard gelatin capsules with swedish orange opaque color cap and swedish orange opaque color body, imprinted 'RDY' on cap and '354' on body with black ink. Rivastigmine tartrate capsules USP, 6 mg are white to off-white powder filled in size ‘2’ hard gelatin capsules with swedish orange opaque color cap and brown opaque color body, imprinted ‘RDY’ on cap and ‘355’ on body with black ink.

4 CONTRAINDICATIONS Rivastigmine tartrate capsules are 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 )

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 Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax 1-202-355-9784) 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 capsules have 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 12 mg/day (n = 1,189) Placebo (n = 868) Rivastigmine tartrate ≥ 6 to 12 mg/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 …

7 DRUG INTERACTIONS Cholinomimetic and anticholinergic drugs: Avoid concomitant use unless clinically necessary. ( 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 capsules are not recommended. 7.2 Cholinomimetic and Anticholinergic Medications Rivastigmine tartrate capsules 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 capsules 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 capsules are used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use of rivastigmine tartrate capsules with beta-blockers is not recommended.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Reproduction studies conducted in pregnant rats and rabbits at oral doses up to 2.3 mg-base/kg/day, or 2 (rat) and 4 (rabbit) times the maximum recommended human dose (MRHD) of 12 mg/day on a mg/m 2 basis, revealed no evidence of teratogenicity. Studies in pregnant rats showed slightly decreased fetal/pup weight at doses that were below the MRHD but usually associated with some maternal toxicity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Rivastigmine and its metabolites are excreted in rat milk following oral administration of rivastigmine; levels of rivastigmine plus metabolites in rat milk are approximately 2 times that in maternal plasma. It is not known whether rivastigmine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivastigmine tartrate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established and therefore the use of rivastigmine in children and adolescents (below 18 years of age) is not recommended. 8.5 Geriatric Use Of the total number of subjects in clinical studies of rivastigmine tartrate, 86 percent were 65 years and older while 46 percent were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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 In patients with moderate to severe renal impairment (glomerular filtration rate [GFR] <50 mL/min), clearance of oral rivastigmine was reduced [see Clinical Pharmacology (12.3)] . Accordingly, such patients may be able to only tolerate lower doses. 8.7 Hepatic Impairment In patients with mild or moderate hepatic impairment (Child-Pugh score 5 to 9), clearance of oral rivastigmine was reduced [see Clinical Pharmacology (12.3)] . Accordingly, such patients may be able to only tolerate lower doses. 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. 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. In patients with low body weight (<50 kg), monitor closely for toxicities (e.g., excessive nausea, vomiting), and consider reducing the dose of Rivastigmine tartrate capsules if such toxicities develop.

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.

11 DESCRIPTION Rivastigmine tartrate is a reversible cholinesterase inhibitor and is known chemically as (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate. Rivastigmine tartrate is commonly referred to in the pharmacological literature as SDZ ENA 713 or ENA 713. It has a molecular formula of C 14 H 22 N 2 O 2 • C 4 H 6 O 6 (hydrogen tartrate salt–hta salt) and a molecular weight of 400.43 g/mol (hta salt). Rivastigmine tartrate is a white to off-white, fine crystalline powder that is very soluble in water, soluble in ethanol and acetonitrile, slightly soluble in n-octanol and very slightly soluble in ethyl acetate. The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 3. Rivastigmine tartrate capsules contain rivastigmine tartrate, USP, equivalent to 1.5 mg, 3 mg, 4.5 mg, and 6 mg of rivastigmine base for oral administration. Inactive ingredients are magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. Each hard-gelatin capsule contains gelatin, titanium dioxide, D & C Red # 28 (1.5 mg), D & C Yellow # 10 (1.5 mg), FD & C Yellow # 6 (1.5 mg, 3 mg, 6 mg), FD & C Red # 40 (6 mg), red iron oxide (4.5 mg, 6 mg) and yellow iron oxide (4.5 mg, 6 mg). The imprinting ink contains shellac, dehydrated alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide and black iron oxide. structure

10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As rivastigmine has a short plasma half-life of about 1 hour and a moderate duration of acetylcholinesterase inhibition of 8 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 a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when coadministered with quaternary anticholinergics such as glycopyrrolate. Due to the short half-life of 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. In a documented case of a 46 mg overdose with rivastigmine tartrate, the patient experienced vomiting, incontinence, hypertension, psychomotor retardation, and loss of consciousness. The patient fully recovered within 24 hours and conservative management was all that was required for treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING Rivastigmine Tartrate Capsules USP Rivastigmine Tartrate Capsules equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of rivastigmine base are available as follows: 1.5 mg Capsule – Pale yellow opaque / pale yellow opaque, size ‘2’ hard gelatin capsules radially imprinted with ‘A’ on cap and ‘116’ on body with black ink, filled with white to off - white free flowing powder. NDC 46708-063-30 Bottle of 30 Capsules NDC 46708-063-60 Bottle of 60 Capsules NDC 46708-063-71 Bottle of 500 Capsules NDC 46708-063-91 Bottle of 1000 Capsules NDC 46708-063-10 Unit Dose Capsules of 100 (Blisters of 10) 3 mg Capsule – Orange opaque / Orange opaque, size ‘2’ hard gelatin capsules radially imprinted with ‘A’ on cap and ‘117’ on body with black ink, filled with white to off - white free flowing powder. NDC 46708-064-30 Bottle of 30 Capsules NDC 46708-064-60 Bottle of 60 Capsules NDC 46708-064-71 Bottle of 500 Capsules NDC 46708-064-91 Bottle of 1000 Capsules NDC 46708-064-10 Unit Dose Capsules of 100 (Blisters of 10) 4.5 mg Capsule – Coral red opaque / coral red opaque, size ‘2’ hard gelatin capsules radially imprinted with ‘A’ on cap and ‘118’ on body with black ink, filled with white to off - white free flowing powder. NDC 46708-065-30 Bottle of 30 Capsules NDC 46708-065-60 Bottle of 60 Capsules NDC 46708-065-71 Bottle of 500 Capsules NDC 46708-065-91 Bottle of 1000 Capsules NDC 46708-065-10 Unit Dose Capsules of 100 (Blisters of 10) 6 mg Capsule – Orange opaque / coral red opaque, size ‘2’ hard gelatin capsules radially imprinted with ‘A’ on cap and ‘119’ on body with black ink, filled with white to off - white free flowing powder. NDC 46708-066-30 Bottle of 30 Capsules NDC 46708-066-60 Bottle of 60 Capsules NDC 46708-066-71 Bottle of 500 Capsules NDC 46708-066-91 Bottle of 1000 Capsules NDC 46708-066-10 Unit Dose Capsules of 100 (Blisters of 10) Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store in a tight container.