RESTILON

Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer's type.

Rivastigmine is a cholinesterase inhibitor that inhibits both butyrylcholinesterase and acetylcholinesterase.

For the treatment of mild to moderate dementia associated with Parkinson's disease or of the Alzheimer's type.

Rivastigmine is a parasympathomimetic and a reversible cholinesterase inhibitor.

An early pathophysiological feature of

Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus.

Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function.

While the precise mechanism of rivastigmine's action is unknown, it is postulated 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.

If this proposed mechanism is correct, rivastigmine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact.

Rivastigmine is rapidly metabolized by cholinesterase-mediated hydrolysis.

Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90.

Renal excretion of the metabolites is the major route of elimination.

Less than 1% of the administered dose is excreted in the feces.

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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 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.

Rivastigmine tartrate capsules are contraindicated in patients with: known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation a previous history of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing Isolated cases of generalized skin reactions have been described in postmarketing experience.

Known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation.

History of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing.

Alzheimer’s Disease: 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 Parkinson’s Disease Dementia (PDD) : 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.

Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening.

Rivastigmine tartrate oral solution and

Rivastigmine tartrate capsules may be interchanged at equal doses 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.

Initiate treatment with the 1.5 mg twice a day with rivastigmine tartrate capsules.

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).

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. 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 to 6) and moderate (Child-Pugh score 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. 2.5 Important Administration Instructions Rivastigmine tartrate oral solution and rivastigmine tartrate capsules may be interchanged at equal doses.

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 – pale yellow opaque / pale yellow opaque size “2” hard gelatin capsules radially imprinted with “A” on cap and “116” on body with black ink, filled with white to off-white free flowing powder.

Bottles of 30 NDC 62332-063-30 Bottles of 60 NDC 62332-063-60 Bottles of 500 NDC 62332-063-71 Bottles of 1000 NDC 62332-063-91 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 62332-063-10 3 mg capsule – orange opaque / orange opaque size “2” hard gelatin capsules radially imprinted with “A” on cap and “117” on body with black ink, filled with white to off-white free flowing powder.

Bottles of 30 NDC 62332-064-30 Bottles of 60 NDC 62332-064-60 Bottles of 500 NDC 62332-064-71 Bottles of 1000 NDC 62332-064-91 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 62332-064-10 4.5 mg capsule – coral red opaque / coral red opaque size “2” hard gelatin capsules radially imprinted with “A” on cap and “118” on body with black ink, filled with white to off-white free flowing powder.

Bottles of 30 NDC 62332-065-30 Bottles of 60 NDC 62332-065-60 Bottles of 500 NDC 62332-065-71 Bottles of 1000 NDC 62332-065-91 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 62332-065-10 6 mg capsule – orange opaque / coral red opaque size “2” hard gelatin capsules radially imprinted with “A” on cap and “119” on body with black ink, filled with white to off-white free flowing powder.

Bottles of 30 NDC 62332-066-30 Bottles of 60 NDC 62332-066-60 Bottles of 500 NDC 62332-066-71 Bottles of 1000 NDC 62332-066-91 Unit Dose (blister pack) Box of 100 (strips of 10) NDC 62332-066-10 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store in a tight container.

There are no adequate data on the developmental risks associated with the use of rivastigmine tartrate in pregnant women.

In animals, no adverse effects on embryo-fetal development were observed at oral doses to 4 times the maximum recommended human dose (MRHD) .

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% to 4% and 15% to 20%, respectively.

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 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis.

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.

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.