RESTILON

Rivastigmine tartrate 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

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 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 is 3.

USP contain rivastigmine tartrate, 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.

Rivastigmine tartrate capsules are an acetylcholinesterase inhibitor indicated for treatment of: Mild-to-moderate dementia of the Alzheimer’s type (AD) Mild-to-moderate dementia associated with Parkinson’s disease (PD) 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).

Lactation QT space extension

QT space extension, family history (d') History of asthma Recent history of myocardial infarction Chronic obstructive Bronchopneumopathy, history(s) Child under 15 years of age Female Pregnancy Congestive heart failure Hepatic impairment Sine disease Patients at risk for digestive ulcer Subject at risk of QT space prolongation Subject at risk of hypokalaemia Subject at risk of hypomagnesaemia Subject at risk of seizure Subject at risk of urinary retention Subject less than 50 kg Extrapyramidal syndrome Cardiac conduction disorder Evolving gastroduodenal ulcer.

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 area under the curve (AUC).

The elimination half-life is about 1.5 hours, with most elimination as metabolites via the urine.

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 (T max ) by 90 minutes lowers C max by approximately 30% and increases AUC by approximately 30%.

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 (V D ) 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.

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).

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.

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.

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 greater than or equal to 60 mL/min); CL/F=1.7 L/min and 4.8 L/min, respectively.

In patients with severe renal impairment (n=8, GFR less than 10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR greater than or equal to 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.

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 to 6), and moderate (n=3, Child-Pugh score to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10).

Following oral rivastigmine administration (up to 12 mg per 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).

Mechanism of action

Rivastigmine is an inhibitor of acetyl and butyrylcholinesterase, carbamate-like, which is thought to facilitate cholinergic neurotransmission by slowing down the degradation of acetylcholine released by functionally intact cholinergic neurons. rivastigmine is therefore likely to have a positive effect on cognitive deficits dependent on these cholinergic pathways during Alzheimer's disease and dementia associated with Parkinson's disease. rivastigmine acts on target enzymes by forming a covalent bonded complex that causes transient inactivation of enzymes.

In the young healthy person, an oral dose of 3 mg results in a decrease of approximately 40% in acetylcholinesterase (AChE) activity in the LCR within an hour and a half after administration.

Enzymatic activity returns to its initial level approximately 9 hours after peak inhibitory activity.

• Liver enzymes (increase)
• Hypersudation (Common)
• Skin reaction at the application site (Common)
• Rash (Common)
• Irritation at the application site Oedema at the application site Pruritus at the application site
• Pruritus Skin Erythema Erythema at the application site Dermatitis at the application site
• Vesicle Urticaria Allergic dermatitis Fever (Common)
• Asthenia (Common)
• Fall (Rare)
• Fatigue Hepatitis Dehydration (Uncommon)
• Anorexia (Common)
• Weight (decrease) (Common)
• Appetite decreased (Common)
• Feeling dizzy (Common)
• Depression (Common)
• Anxiety (Common)
• Mental confusion (Common)
• Aggressiveness (Uncommon)
• Agitation (Common)
• Hallucination
• Nightmare Insomnia Nervousness Bradycardia (Uncommon)
• Malaise (Common)
• Syncope (Common)
• Angor (Rare)
• Tachycardia Sine disease Atrial fibrillation Hypertension Atrialculoventric block
• Heart failure Abdominal pain (Common)
• Nausea (Common)
• Vomiting (Common)
• Dyspepsia (Common)
• Diarrhoea (Common)
• Gastric ulcer (Uncommon)
• Gastrointestinal haemorrhage (Very rare)
• Duodenal Ulcer (Rare)
• Pancreatitis Esophagus cut Headache (Common)
• Psychomotor hyperactivity (Uncommon)
• Extrapyramidal syndrome (Very rare)
• Somnolence Trembling Convulsions Parkinson's disease (aggravation)
• Urinary incontinence (Common)
• Urinary infection (Common).

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.