Rivastigmine Tartrate

Brand names: Rivastigmine Tartrate, RIVASTIGMINE TARTRATE

Warnings

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 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 a dose of 1.5 mg twice a day and titrated to their maintenance dose. If treatment is interrupted for longer than 3 days, treatment should be reinitiated with the lowest daily dose [see Dosage and Administration ( 2.3 )] to reduce the possibility of severe vomiting and its potentially serious sequelae (e.g., there has been one postmarketing report of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment with a 4.5-mg dose after 8 weeks of treatment interruption). Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration. 5.2 Allergic Dermatitis There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). Treatment should be discontinued if disseminated allergic dermatitis occurs [see Contraindications ( 4 )] . Patients and caregivers should be instructed accordingly [see Patient Counseling Information 17 )] . In patients who develop application site reactions, suggestive of allergic contact dermatitis to rivastigmine tartrate patch and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form. 5.3 Other Adverse Reactions from Increased Cholinergic Activity Neurologic Effects Extrapyramidal Symptoms : Cholinomimetics, including rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson's disease who were treated with rivastigmine tartrate capsules. Seizures : Drugs that increase cholinergic activity are believed to have some potential for causing seizures. However, seizure activity also may be a manifestation of Alzheimer's disease. Peptic Ulcers/Gastrointestinal Bleeding Cholinesterase inhibitors, including rivastigmine, may be expected to increase gastric acid secretion due to increased cholinergic activity. Monitor patients using rivastigmine tartrate capsules for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Use with Anesthesia Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Cardiac Conduction Effects Because rivastigmine increases cholinergic activity, use of rivastigmine may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, rivastigmine was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or electrocardiogram (ECG) abnormalities. Syncopal episodes have been reported in 3% of patients receiving 6 mg to 12 mg per day of rivastigmine tartrate capsules, compared to 2% of placebo patients. Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction. Pulmonary Effects Drugs that increase cholinergic activity, including rivastigmine, should be used with care in patients with a history of asthma or obstructive pulmonary disease. 5.4 Impairment in Driving or Use of Machinery Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions. During treatment with the rivastigmine tartrate capsules, routinely evaluate the patient’s ability to continue driving or operating machinery.

Contraindications

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 )

Overdose

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. 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. A fatal outcome has been rarely reported with rivastigmine.

Drug interactions

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.

Uses

1 INDICATIONS & USAGE Rivastigmine tartrate is an acetylcholinesterase inhibitor indicated for treatment of: • Mild-to-moderate dementia of the Alzheimers type (AD) ( 1.1 ) • Mild-to-moderate dementia associated with Parkinsons 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).

Dosage forms & strengths

POWDER CAPSULE
RIVASTIGMINE TARTRATE 25 kg/25kg RIVASTIGMINE TARTRATE 3 mg/1 RIVASTIGMINE TARTRATE 4.5 mg/1 RIVASTIGMINE TARTRATE 1.5 mg/1 RIVASTIGMINE TARTRATE 6 mg/1 RIVASTIGMINE TARTRATE 50 kg/50kg RIVASTIGMINE TARTRATE 1 kg/kg RIVASTIGMINE TARTRATE 10 kg/10kg

2 DOSAGE & 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 ( 2.1 ) 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 ( 2.2 ) Rivastigmine tartrate capsules 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.

All identified pills

Side effects

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 Macleods Pharma USA, Inc., at 1-888-943-3210 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 capsules cholinergic effects. These include nausea, vomiting, anorexia, dyspepsia, and asthenia. Gastrointestinal Adverse Reactions Rivastigmine tartrate capsules 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 capsules 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 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 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 Placebo Rivastigmine tartrate ≥6 to 12 mg/day Placebo Rivastigmine tartrate ≥6 to 12 mg/day Placebo (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 capsules 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 Event Rivastigmine tartrate (6 to 12 mg/day) (n=1,189) Placebo (n=868) Percent of Patients with any Adverse Reaction 92 79 Autonomic Nervous System Sweating Increased 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 an rivastigmine tartrate capsules 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 capsules-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 capsules-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 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 an rivastigmine tartrate capsules 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 capsules 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 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 capsules 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 eactions 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 0.0% placebo). Adverse Reactions Observed at an Incidence of at Least 2% Table 3 lists treatment-emergent signs and symptoms that were reported 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 capsules 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 Event 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 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

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