rivastigmine 6 mg capsule generic exelon

Uses

Alzheimer's Disease

Rivastigmine is used orally and transdermally for the management of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease). Efficacy of orally administered rivastigmine has been evaluated in 2 placebo-controlled clinical trials each of 26 weeks' duration utilizing a dual outcome assessment strategy; changes in cognitive performance were assessed by various instruments, including the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), and changes in overall clinical effects were assessed using the Clinician's Interview-Based Impression of Change (CIBIC) that required the use of caregiver information (CIBIC plus). (For additional information on ADAS cog and CIBIC plus, see Uses: Alzheimer's Disease in Donepezil Hydrochloride 12:04.) Two dosage ranges (1-4 and 6-12 mg daily administered orally) were used in each study. Rivastigmine 6-12 mg daily was found to be more effective than placebo or rivastigmine 1-4 mg daily in both studies for improvements in cognitive function and overall clinical status as assessed by the ADAS cog and CIBIC plus scales. A third placebo-controlled clinical trial utilizing forced titration to fixed dosages (3, 6, or 9 mg daily administered orally) was performed employing the same outcome assessment tools. Rivastigmine was more effective than placebo at the 2 higher dosages for mean change from baseline on the ADAS cog scores. However, no substantial differences were observed between any of the rivastigmine dosage groups and placebo when CIBIC plus scores were compared.

Rivastigmine transdermal system has been evaluated for the management of dementia of the Alzheimer's type in a single, placebo-controlled, international clinical trial of 24 weeks' duration utilizing a dual outcome assessment strategy; changes in cognitive performance were assessed by various instruments, including the cognitive subscale of ADAS cog, and changes in overall clinical effects were assessed using the Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), which is a more standardized form of CIBIC plus. Study participants were randomized to receive a target dose of one transdermal system delivering rivastigmine 9.5 mg/24 hours, one system delivering 17.4 mg/24 hours, rivastigmine 6 mg orally twice daily, or placebo. The first 16 weeks of the study was a dosage escalation phase, with initial dosages of one transdermal system delivering 4.6 mg/24 hours applied once daily or 3 mg daily (administered as 1.5 mg orally twice daily) gradually increased over 16 weeks to the target dosage; the 16-week dose escalation phase was followed by an 8-week maintenance phase. Results of this study indicate that efficacy of a system delivering 9.5 mg/24 hours was similar to that of orally administered rivastigmine. At week 24, rivastigmine transdermal system delivering 9.5 mg/24 hours, the transdermal system delivering 17.4 mg/24 hours, and orally administered rivastigmine (6 mg twice daily) were more effective than placebo for mean change from baseline on the ADAS cog scores. In addition, rivastigmine transdermal system delivering 9.5 mg/24 hours and orally administered rivastigmine were more effective than placebo for mean change from baseline on the ADCS-CGIC scale; no substantial differences were observed between the transdermal system delivering 17.4 mg/ 24 hours and placebo on change on the ADCS-CGIC scale.

For additional information on the management of Alzheimer's disease, .

Dementia Associated with Parkinsonian Syndrome

Rivastigmine is used orally and transdermally for the management of mild to moderate dementia associated with Parkinson's disease. Dementia associated with Parkinson's disease generally is characterized by impairments in executive function, memory retrieval, and attention in patients with an established diagnosis of Parkinson's disease. However, the diagnosis of dementia associated with Parkinson's disease can be made without documenting these specific deficits in patients in whom a progressive dementia syndrome occurs at least 2 years after a diagnosis of Parkinson's disease has been made and in whom other causes of dementia have been ruled out.

Efficacy of orally administered rivastigmine has been evaluated for the management of dementia associated with idiopathic Parkinson's disease in a single, placebo-controlled, international clinical trial of 24 weeks' duration in patients with mild to moderate dementia with onset at least 2 years after the initial diagnosis of idiopathic Parkinson's disease. The first 16 weeks of the study was a dosage escalation phase, with initial dosages of 3 mg daily (administered orally as 1.5 mg twice daily) gradually increased by increments of 3 mg daily at intervals of at least 4 weeks up to a maximum dosage of 12 mg daily. The highest tolerated dosage was then maintained for the remainder of the study; dosages could be adjusted as needed because of adverse effects. The trial used a dual outcome assessment strategy; changes in cognitive performance were assessed by ADAS cog and changes in overall clinical effects were assessed using the Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), which is a more standardized form of CIBIC plus. (For additional information on ADAS cog and CIBIC plus, see Uses: Alzheimer's Disease in Donepezil Hydrochloride 12:04.) Rivastigmine (mean final oral dosage 8.6 mg daily) was found to be more effective than placebo for improvements in cognitive performance and in overall clinical efficacy as assessed by the ADAS cog and ADCS-CGIC scales, respectively.

Dosage and Administration

Administration

Rivastigmine tartrate is administered orally twice daily. Rivastigmine is administered percutaneously by topical application of a transdermal system.

When rivastigmine is administered orally, administration with food has been shown to reduce the rate and increase the extent of GI absorption, and administration of the drug in the morning and evening with food is recommended, since the incidence of adverse GI effects (e.g., nausea, vomiting) may be related to high peak plasma concentrations.

The oral solution and capsules may be interchanged at equal doses.

The oral solution should be administered using the oral dosing syringe according to the patient instructions provided by the manufacturer.

Patients receiving transdermal rivastigmine therapy or their caregivers should be carefully instructed in the use of the transdermal system. To expose the adhesive surface of the system, the protective liner should be peeled and discarded prior to administration. The transdermal system is applied topically to a dry, hairless area of intact skin, preferably the back, by firmly pressing the system with the adhesive side touching the skin; placement on the back is recommended to reduce the risk that the system could be removed by the patient. Alternatively, the transdermal system may be applied to the upper arm or chest. The rivastigmine transdermal system is worn continuously for 24 hours; subsequent systems are applied after removal of the previous system. To minimize and/or prevent potential skin irritation, each system should be applied to a different site, with an interval of at least 14 days between applications to a particular site. The application site should not be red, irritated, or cut. The transdermal system should not be applied to areas where the system might be rubbed off. If the system should inadvertently come off during the period of use, a new system may be applied; the application schedule employed should be continued.

Dosage

Dosage of rivastigmine tartrate is expressed in terms of rivastigmine.

Alzheimer's Disease

The recommended initial oral dosage of rivastigmine for the management of mild to moderate dementia of the Alzheimer's type in adults is 1.5 mg twice daily. If well tolerated, this dosage may be increased after a minimum of 2 weeks to 3 mg twice daily. Subsequent increases to 4.5 mg twice daily and then to 6 mg twice daily should be attempted after a minimum of 2 weeks of treatment at the previous dosage. In clinical studies, a dosage of 6-12 mg daily (administered as doses of 3-6 mg twice daily) was effective. There is evidence from placebo-controlled studies that dosages at the higher end of this range may be more beneficial. The maximum recommended dosage is 12 mg daily (administered as doses of 6 mg twice daily).

When transdermal rivastigmine is used for the management of mild to moderate dementia of the Alzheimer's type in adults, the recommended initial dosage is one system delivering 4.6 mg/24 hours applied once daily. If well tolerated, this dosage may be increased after a minimum of 4 weeks to one system delivering 9.5 mg/24 hours applied once daily. The maximum recommended daily dosage is 9.5 mg/24 hours.

If patients are unable to tolerate adverse effects associated with rivastigmine, the patient should be instructed to discontinue the drug for several doses and then resume therapy at the same or the immediately preceding (lower) dosage in the titration regimen. However, if therapy is interrupted for more than several days, the drug should be restarted using the recommended initial dosage (i.e., 1.5 mg twice daily or one system delivering 4.6 mg/24 hours applied once daily) and titration schedule until the previous maintenance dosage is reached to decrease the risk of severe vomiting and related sequelae (e.g., spontaneous esophageal rupture). Clinical experience with reinitiating rivastigmine therapy using dosages higher than the initial dosage recommended by the manufacturer is limited.(See Warnings: GI Effects.)

Transdermal Dosage in Patients Transferred from Oral Therapy

If the rivastigmine oral dosage has been less than 6 mg daily, the initial recommended dosage of the transdermal system is one system delivering 4.6 mg/24 hours applied once daily. If the rivastigmine oral dosage has been 6-12 mg daily, the initial recommended dosage of the transdermal system is one system delivering 9.5 mg/24 hours applied once daily. The first transdermal system should be applied the day after the last oral rivastigmine dose.

Dementia Associated with Parkinsonian Syndrome

The recommended initial oral dosage of rivastigmine for the management of mild to moderate dementia associated with Parkinson's disease in adults is 1.5 mg twice daily. If well tolerated, this dosage may be increased after a minimum of 4 weeks to 3 mg twice daily. Subsequent increases to 4.5 mg twice daily and then to 6 mg twice daily should be attempted after a minimum of 4 weeks of treatment at the previous dosage. In the single controlled clinical study, a dosage of 3-12 mg daily (administered as doses of 1.5-6 mg twice daily) was effective.

When transdermal rivastigmine is used for the management of mild to moderate dementia associated with Parkinson's disease, the recommended initial dosage is one system delivering 4.6 mg/24 hours applied once daily. If well tolerated, this dosage may be increased after a minimum of 4 weeks to one system delivering 9.5 mg/24 hours applied once daily. The maximum recommended daily dosage is 9.5 mg/24 hours.

If patients are unable to tolerate adverse effects associated with rivastigmine, the patient should be instructed to discontinue the drug for several doses and then resume therapy at the same or the immediately preceding (lower) dosage in the titration regimen. However, if therapy is interrupted for more than several days, the drug should be restarted using the recommended initial dosage (i.e., 1.5 mg twice daily or one system delivering 4.6 mg/24 hours applied once daily) and titration schedule until the previous maintenance dosage is reached to decrease the risk of severe vomiting and related sequelae (e.g., spontaneous esophageal rupture). Clinical experience with reinitiating rivastigmine therapy using dosages higher than the initial dosage recommended by the manufacturer is limited.(See Warnings: GI Effects.)

Transdermal Dosage in Patients Transferred from Oral Therapy

If the rivastigmine oral dosage has been less than 6 mg daily, the initial recommended dosage of the transdermal system is one system delivering 4.6 mg/24 hours applied once daily. If the rivastigmine oral dosage has been 6-12 mg daily, the initial recommended dosage of the transdermal system is one system delivering 9.5 mg/24 hours applied once daily. The first transdermal system should be applied the day after the last oral rivastigmine dose.

Special Populations

In clinical studies, oral clearance was reduced 60 or 65% after single or multiple doses, respectively, in patients with hepatic impairment. In patients with moderate or severe renal impairment, oral clearance was reduced 64% or increased 43%, respectively. The unexpected increase in clearance in patients with severe renal impairment has not been explained. However, the manufacturer states that dosage adjustment may not be necessary in patients with renal or hepatic impairment since the dosage of rivastigmine is individually titrated to adverse effect tolerability. The manufacturer currently makes no specific recommendations for dosage adjustment based on age, gender, or race.

Cautions

Contraindications

Known hypersensitivity to rivastigmine or any ingredient in the formulation. Although there are no reports of cross-sensitivity to date, the manufacturer states that the drug also is contraindicated in patients with known hypersensitivity to other carbamates.

Warnings/Precautions

Warnings

GI Effects

Rivastigmine is associated with clinically important adverse GI effects, including nausea and vomiting, diarrhea, anorexia, and weight loss. In controlled trials, 47% of patients treated with oral rivastigmine in a dosage of 6-12 mg daily developed nausea, and 31% developed at least one episode of vomiting. In controlled trials that evaluated rivastigmine transdermal therapy, 7% of patients treated with the recommended dosage (one system delivering 9.5 mg/24 hours daily) developed nausea, and 6% developed vomiting. Discontinuance of rivastigmine because of nausea, vomiting, or anorexia was reported in 8, 5, or 3% of patients, respectively, receiving orally administered rivastigmine 6-12 mg daily in clinical studies.

Severe vomiting and spontaneous rupture of the esophagus (Boerhaave's syndrome) were reported in a patient who resumed therapy by erroneously taking a single higher than recommended initial dose (i.e., 4.5 mg administered orally) of rivastigmine after therapy had been interrupted for 8 weeks. Because these adverse effects may have been caused by the lack of titration of the drug, the manufacturer has recommended strict adherence to prescribed initial dosages and titration schedules, particularly when reinitiating therapy following temporary interruptions lasting longer than several days.(See Dosage and Administration: Dosage.)

Peptic Ulcers/GI Bleeding

Cholinesterase inhibitors such as rivastigmine may increase gastric acid secretion. Monitor closely for manifestations of active or occult GI bleeding, especially in patients at increased risk (e.g., history of ulcer disease, concomitant nonsteroidal anti-inflammatory agent [NSAIA] therapy).

Cardiovascular Effects

Since cholinesterase inhibitors may produce bradycardia or other vagotonic effects on the heart, rivastigmine should be used with caution in patients with sick sinus syndrome or other supraventricular cardiac conduction abnormalities.

Genitourinary Effects

Although not reported in clinical studies with rivastigmine, cholinomimetic agents may cause urinary obstruction.

Seizures

Potential for increased risk of seizures secondary to cholinergic activity (seizures also may be a manifestation of Alzheimer's disease).

Respiratory Effects

Like other drugs that increase cholinergic activity, use with caution in patients with a history of asthma or obstructive pulmonary disease.

General Precautions

Extrapyramidal Reactions

Like other cholinomimetic agents, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening in patients with Parkinson's disease, including an increased incidence or intensity of tremor, reported.

Effects on Ability to Drive and Use Heavy Machinery

Dementia may cause gradual impairment of ability to drive or operate heavy machinery; adverse effects (e.g., dizziness, asthenia, fatigue) of rivastigmine also may be detrimental to these functions. The ability to drive or use heavy machinery should be evaluated by the treating clinician on a routine basis.

Low-weight Individuals

When rivastigmine transdermal system is used, patients with body weight less than 50 kg may experience more adverse effects and may be more likely to discontinue therapy due to adverse effects. If the dosage exceeds the maximum recommended dosage, patient with low body weight should be closely supervised by the clinician.

Specific Populations

Pregnancy

Category B. (See Users' Guide.)

Lactation

Not known whether rivastigmine is distributed into milk; use in nursing women is not recommended.

Pediatric Use

Currently not indicated.

Common Adverse Effects

In clinical trials of oral rivastigmine in patients with dementia of the Alzheimer's type, adverse effects occurring in 5% or more of patients receiving rivastigmine and more than twice as frequently as among those receiving placebo included nausea, vomiting, anorexia, dyspepsia, and asthenia. Dizziness, diarrhea, headache, abdominal pain, accidental trauma, fatigue, insomnia, confusion, urinary tract infection, depression, malaise, somnolence, constipation, and anxiety occurred in at least 5% of patients receiving rivastigmine and more frequently than in patients receiving placebo in clinical studies in patients with dementia of the Alzheimer's type.

In clinical trials of oral rivastigmine in patients with dementia associated with Parkinson's disease, adverse effects occurring in 5% or more of patients receiving rivastigmine and more than twice as frequently as among those receiving placebo included nausea, vomiting, tremor, anorexia, and dizziness.

In a clinical trial that evaluated rivastigmine transdermal therapy in patients with dementia of the Alzheimer's type, nausea, vomiting, and diarrhea occurred in at least 5% of patients receiving rivastigmine (one system delivering 9.5 mg/24 hours) and more frequently than in patients receiving placebo. Most patients experienced no, slight, or mild skin irritation.

Drug Interactions

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely with drugs metabolized by cytochrome P-450 (CYP) isoenzymes or with cytochrome P-450 enzyme inducers or inhibitors.

Anticholinergic Agents

Potential pharmacologic interaction (antagonistic effects).

Cholinomimetics and Other Cholinesterase Inhibitors

Potential pharmacologic interaction (additive effects).

Skeletal Muscle Relaxants

Potential pharmacologic interaction (exaggerated response to succinylcholine-type muscle relaxants during surgery).

Smoking

Potential pharmacokinetic interaction (increased oral rivastigmine clearance).

Protein-bound Drugs

Pharmacokinetic interaction unlikely.

Pharmacokinetics

Absorption

Bioavailability

Oral: Rivastigmine is rapidly and completely absorbed from the GI tract. Absolute bioavailability is approximately 36-40%. Peak plasma concentrations attained in approximately 1 hour following oral administration.

Transdermal system: Peak plasma concentrations are attained in approximately 8 hours.

At steady-state, rivastigmine exposure (area under the plasma concentration-time curve [AUC]_24h) in individuals receiving a transdermal system delivering 9.5 mg/24 hours was approximately the same as that achieved in individuals receiving the 6-mg capsule twice daily.

Food

Oral: Food delays absorption by 90 minutes, lowers peak plasma concentration by approximately 30%, and increases extent of absorption by approximately 30%.

Plasma Concentrations

High peak plasma concentrations possibly associated with adverse GI effects (e.g., nausea, vomiting). Peak plasma concentrations achieved following administration of a transdermal system delivering 9.5 mg/24 hours were approximately 70% lower than concentrations achieved following oral administration of 6 mg twice daily.

In low-weight individuals (weight 35 kg), plasma concentrations are substantially increased compared with normal-weight individuals (weight 65 kg).

Distribution

Extent

Widely distributed throughout the body; peak CSF concentrations attained within 1.4-2.6 hours. Not known whether rivastigmine is distributed into milk.

Plasma Protein Binding

About 40%.

Elimination

Metabolism

Rapidly and extensively metabolized, principally via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. CYP enzyme system is minimally involved in metabolism.

Elimination Route

Excreted principally in urine as metabolites.

Half-life

Oral administration: Approximately 1.3-2 hours..

Transdermal system: Approximately 3.4 hours.

Special Populations

In patients with mild to moderate hepatic impairment, oral clearance reduced 60-65%.

Mean oral clearance reduced 64% in patients with moderate renal impairment but increased 43% in those with severe renal impairment.