RIVASTIGMINE TARTRATE (Page 2 of 5)

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.

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)].

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 Capsules Using a Forced-Dose Titration
Study Phase Titration Maintenance Overall
Rivastigmine tartrate capsules ≥6 to 12 mg/day (n=1,189) Placebo (n=868) Rivastigmine tartrate capsules ≥6 to 12 mg/day (n=987) Placebo (n=788) Rivastigmine tartrate capsules ≥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 ≥2% and at a 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 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 0.0% 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 ≥2% and Occurring at Rate Greater than Placebo in Clinical Trials
Body System/Adverse Reaction Active-Controlled Study Placebo-Controlled Study
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.

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