RIVASTIGMINE TARTRATE (Page 3 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of rivastigmine tartrate. 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.

7 DRUG INTERACTIONS

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 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 per day on a mg/m2 basis, revealed no evidence of teratogenicity. 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. The use of rivastigmine tartrate in pediatric patients (below 18 years of age) is not recommended.

8.5 Geriatric Use

Of the total number of patients in clinical studies of rivastigmine tartrate, 86 % were 65 years and older while 46 % were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, 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

Patients with moderate to severe renal impairment may be able to only tolerate lower doses [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with mild or moderate hepatic impairment may be able to only tolerate lower doses [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. No data are available on the use of rivastigmine tartrate 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 [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

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 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.

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 is commonly referred to in the pharmacological literature as SDZ ENA 713 or ENA 713. It has an empirical formula of C14 H22 N2 O2 • C4 H6 O6 (hydrogen tartrate salt–hta salt) and a molecular weight of 400.42 (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 3.0.
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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 hypromellose, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. Each hard-gelatin capsule contains gelatin, titanium dioxide and red and/or yellow iron oxides. Imprinting ink contains: shellac, propylene glycol, black iron oxide and potassium hydroxide.
Rivastigmine tartrate capsules meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

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.

12.2 Pharmacodynamics

After a 6-mg dose of rivastigmine, anticholinesterase activity is present in cerebrospinal fluid (CSF) for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing.

In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.

12.3 Pharmacokinetics

Rivastigmine shows linear pharmacokinetics up to 3 mg twice a day but is nonlinear at higher doses. Doubling the dose from 3 mg to 6 mg twice a day results in a 3-fold increase in AUC. The elimination half-life is about 1.5 hours, with most elimination as metabolites via the urine.

Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. Absolute bioavailability after a 3-mg dose is about 36%. Administration of rivastigmine tartrate with food delays absorption (tmax ) by 90 minutes lowers Cmax by approximately 30% and increases AUC by approximately 30%.


Distribution
Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg.

Metabolism
Rivastigmine is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. Based on evidence from in vitro and animal studies, the major cytochrome P450 isozymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions related to cytochrome P450 have been observed in humans.

Elimination
The major pathway of elimination is via the kidneys. Following administration of 14 C-rivastigmine to 6 healthy volunteers, total recovery of radioactivity over 120 hours was 97% in urine and 0.4% in feces. No parent drug was detected in urine. The sulfate conjugate of the decarbamylated metabolite is the major component excreted in urine and represents 40% of the dose. Mean oral clearance of rivastigmine is 1.8 ± 0.6 L/min after 6 mg twice a day.

Age
Following a single 2.5-mg oral dose to elderly volunteers (60 years and older, n=24) and younger volunteers (n=24), mean oral clearance of rivastigmine was 30% lower in elderly (7 L/min) than in younger subjects (10 L/min).

Gender and Race
Population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, 4 Asian, and 12 Other) affected clearance of the drug.

Body Weight
A relationship between drug exposure at steady-state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Rivastigmine exposure is higher in subjects with low body weight. 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.

Renal Impairment
Following a single 3-mg dose, mean oral clearance of rivastigmine is 64% lower in moderately impaired renal patients (n=8, GFR=10 to 50 mL/min) than in healthy subjects (n=10, GFR ≥60 mL/min); Cl/F=1.7 L/min and 4.8 L/min, respectively. In patients with severe renal impairment (n=8, GFR <10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR ≥60 mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively. For unexplained reasons, the severely impaired renal patients had a higher clearance of rivastigmine than moderately impaired patients.
Hepatic Impairment
Following a single 3-mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg twice a day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10).

Smoking
Following oral rivastigmine administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers).
Drug Interaction Studies

Effect of Rivastigmine on the Metabolism of Other Drugs
Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6.
No pharmacokinetic interaction was observed between rivastigmine taken orally and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine.


Effect of Other Drugs on the Metabolism of Rivastigmine
Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.
Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), beta-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), NSAIDs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15).

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