Rivastigmine Tartrate
FDA Drug Information • Also known as: Rivastigmine Tartrate
- Brand Names
- Rivastigmine Tartrate
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Rivastigmine tartrate USP 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 USP is commonly referred to in the pharmacological literature as SDZ ENA 713 or ENA 713. It has an empirical 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 USP 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 3.0. Rivastigmine Tartrate Capsules USP 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 hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, and silicon dioxide. Each hard-gelatin capsule contains gelatin, titanium dioxide, purified water, sodium lauryl sulfate and red and/or yellow iron oxides. structureWhat Is Rivastigmine Tartrate Used For?
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 and Administration
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...Side Effects (Adverse Reactions)
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...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.
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 )Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of rivastigmine in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 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%-4% and 15%-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.
Overdosage
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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Rivastigmine tartrate Capsules Rivastigmine tartrate capsules USP equivalent to 1.5 mg, 3 mg, 4.5 mg, or 6 mg of rivastigmine base are available as follows: 1.5 mg capsule: Yellow/yellow, size "2", hard gelatin capsules containing white to off-white powder with "CL7" on cap and "1.5 mg" on body imprinted with red ink. Bottles of 60 NDC 33342-089-09 Bottles of 500 NDC 33342-089-15 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 33342-089-12 Unit Dose (blister pack) Box of 30 (strips of 10) NDC 33342-089-06 3 mg capsule: Orange/orange, size "2", hard gelatin capsules containing white to off-white powder with "CL8" on cap and "3 mg" on body imprinted with red ink. Bottles of 60 NDC 33342-090-09 Bottles of 500 NDC 33342-090-15 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 33342-090-12 Unit Dose (blister pack)Box of 30 (strips of 10) NDC 33342-090-06 4.5 mg capsule: Red/red, size "2", hard gelatin capsules containing white to off-white powder with "CL9" on cap and "4.5 mg" on body imprinted with white ink. Bottles of 60 NDC 33342-091-09 Bottles of 500 NDC 33342-091-15 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 33342-091-12 Unit Dose (blister pack) Box of 30 (strips of 10) NDC 33342-091-06 6 mg capsule: Red/orange, size "2", hard gelatin capsules containing white to off-white powder with "CL10" on cap and "6 mg" on body imprinted with white ink. Bottles of 60 NDC 33342-092-09 Bottles of 500 NDC 33342-092-15 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 33342-092-12 Unit Dose (blister pack) Box of 30 (strips of 10) NDC 33342-092-06 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store in a tight container.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.