Trivacin

Trivacin

rivastigmine

Manufacturer:

Luye Pharma

Distributor:

Berlin Pharm

Marketer:

Berlin Pharm
Full Prescribing Info
Contents
Rivastigmine.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Rivastigmine tartrate, a carbamate derivative, is an intermediate-acting, reversible cholinesterase inhibitor that is structurally related to physostigmine but unrelated to donepezil or tacrine. The precise mechanism(s) of action of rivastigmine in patients with dementia of the Alzheimer's type (Alzheimer's disease) and dementia associated with Parkinson's disease has not been full elucidated. The drug is an anticholinesterase agent that binds reversibly with and inactivates cholinesterases (e.g. acetylcholinesterase, butyrylcholinesterase), thus inhibiting hydrolysis of acetylcholine and increasing the concentration of acetylcholine at cholinergic synapses. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with that in peripheral tissues.
Metabolism of rivastigmine is rapid and extensive and occurs principally via cholinesterase-mediated hydrolysis to the decarbamylated metabolite, which is tenfold less active than rivastigmine. The drug is only minimally metabolized by cytochrome P-450 (CYP) isoenzymes.
Pharmacodynamics: 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.
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 that placebo for mean change from baseline on the Alzheimer's Disease Assessment Scale-Cognition (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 Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Chage (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.
Pharmacokinetics: Absorption: After the first dose, there is a lag time of 0.5 to 1 hours in the absorption of rivastigmine for the rivastigmine transdermal patch. Concentrations then rise slowly; typically reaching a maximum after 8 hours, although maximum values (Cmax) are often reached at later times as well (10 to 16 h). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady-state, though levels are approximately 60% to 80% of peak levels. Fluctuation (between Cmax and minimum concentration (Cmin)) is lower for the rivastigmine transdermal than for the oral formulation. Rivastigmine 9.5 mg/24 h transdermal patch exhibited exposure approximately the same as that provided by an oral dosage of 6 mg twice daily (i.e. 12 mg/day).
Intersubject variability in exposure was lower (43% to 49%) for the rivastigmine transdermal formulation as compared with the oral formulation (73% to 103%).
A relationship between drug exposure at steady state (rivastigmine and metabolite NAP116-90) and body weight was observed in patients with Alzheimer dementia. Compared with a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 100 kg, the concentrations are approximately halved. The effect of body weight on drug exposure suggests special attention to patients with very low body weight during up-titration.
Over a 24-hour dermal application, approximately 50% of the drug load is released for the system.
Exposure (area under the curve [AUC]) to rivastigmine (and metabolite NAP266-90) was highest when the transdermal patch was applied to the upper back, chest or upper arm. Two other sites (abdomen and thigh) could be used if none of the 3 other sites is available, but keep in mind that the rivastigmine plasma exposure associated with these sites was approximately 20% to 30% lower.
There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer disease upon multiple dosing.
Distribution: Rivastigmine is weakly bond to plasma protein (approximately 40%) over 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 extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (less than 10%). Based on evidence from in-vitro and animal studies, the major CYP-450 isoenzymes are minimally involved in rivastigmine metabolism.
The metabolite-to-parent AUC ratio was approximately 0.7 after rivastigmine transdermal application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following transdermal application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin.
Excretion: Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after transdermal removal. Renal clearance was approximately 2.1 to 2.8 L/h.
Special Populations: Renal function impairment: No study was conducted with rivastigmine transdermal in subjects with renal function impairment.
However, dosage adjustment may not be necessary in patients with renal function impairment, as the dose of the drug is individually titrated to tolerability.
Hepatic function impairment: No pharmacokinetic study was conducted with rivastigmine transdermal in subjects with hepatic function impairment. Dosage adjustment is not necessary in patients with hepatic function impairment, as the dose of the drug is individually titrated to tolerability.
Gender and race: No specific pharmacokinetic data was conducted to investigate the effect of gender and race on the disposition of rivastigmine, but a population pharmacokinetic analysis indicates that gender (277 men and 348 woman) and race (575 white, 34 black, 4 Asian and 12 other) did not affect the clearance of rivastigmine administered orally. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of rivastigmine transdermal.
Nicotine: Population pharmacokinetic data showed that nicotine use increases the oral clearance of rivastigmine by 23% (75 smokers and 549 nonsmokers). No dose adjustment is necessary, as the dose of the drug is individually titrated to tolerability.
Indications/Uses
Alzheimer disease: For the treatment of mild to moderate dementia of the Alzheimer type.
Parkinson disease dementia: For the treatment of mild to moderate dementia associated with Parkinson disease.
Dosage/Direction for Use
Recommended Dose: General dosing considerations: Patients with a body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue treatment because of adverse reactions. Particular caution should be exercised in titrating these patients above the recommended maintenance dose of the rivastigmine 9.5 mg/24 hours transdermal patch.
Adults: Initial dosage: 4.6 mg/24 hours.
Maximum dose: 9.5 mg/24 hours.
Dosage titration: After a minimum of 4 weeks of treatment and if well tolerated, the dose should be increased to the rivastigmine 9.5 mg/24 hours transdermal patch.
Maintenance dose: 9.5 mg/24 hours. Higher doses confer no appreciable additional benefit and are associated with a significant increase in the incidence of adverse reactions.
Dosage adjustment: If adverse reactions (e.g., diarrhea, loss of appetite, nausea, vomiting) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several days and then restart at the same or next lower dose level. If treatment is interrupted for longer than several days, treatment should be reinitiated with the lowest daily dose and titrated as previously described.
Conversion: Patients treated with rivastigmine capsules or oral solution may be switched to rivastigmine transdermal according to the following: A patient who is on a total daily dose of oral rivastigmine less than 6 mg can be switched to the rivastigmine 4.6 mg/24 hours transdermal patch.
A patient who is on a total daily dose of oral rivastigmine 6 to 12 mg may be directly switched to the rivastigmine 9.5 mg/24 hours transdermal patch.
It is recommended to apply the first transdermal patch on the day following the last oral dose.
Dementia associated with Parkinson disease - see Alzheimer dementia for dosing.
Special Populations: Renal impairment: No dose adjustment is necessary for patients with renal impairment.
Paediatric patients: Children and adolescents (age below 18 years): Rivastigmine is not recommended for use in children.
Mode of Administration: Rivastigmine transdermal should be applied once a day to clean, dry, hairless, intact healthy skin in a place that will not be rubbed by tight clothing. The upper or lower back is recommended as the site of application because the transdermal patch is less likely to be removed by the patient; however, when sites on the back are not accessible, the transdermal patch can be applied to the upper arm or chest. The transdermal patch should not be applied to skin that is red, irritated or cut. It is recommended that the site of transdermal patch application be changed daily to avoid potential irritation, although consecutive transdermal patches can be applied to the same anatomic site (e.g. another spot on the upper back). The same site should not be used within 14 days. The transdermal patch should be replaced with a new one every 24 hours.
The transdermal patch should be pressed down firmly until the edges stick well. The transdermal patch can be used in situations that include bathing and hot weather. To prevent interference with the adhesive properties of the transdermal patch, it should not be applied to a skin area where cream, lotion or powder has been recently applied.
If patch fall off, apply a new patch for the rest of the day, then replace the patch the next day at the same time usual.
Overdosage
Overdose: Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by bradycardia, collapse, convulsions, hypotension, respiratory depression, salivation, severe nausea, sweating and vomiting. 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.
Treatment: Because rivastigmine has a plasma half-life of about 3.4 hours after transdermal administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose, the transdermal patch be immediately removed and no transdermal patch applied for the next 24 hours.
Due to the short plasma elimination half-life of rivastigmine after transdermal administration, dialysis (hemodialysis, hemofiltration or peritoneal dialysis) would not be clinically indicated in the event of an overdose.
In overdose accompanied by severe nausea and vomiting, consider the use of antiemetics. In a documented case of an oral 46 mg overdose with rivastigmine, the patient experienced hypertension, incontinence, loss of consciousmine, psychomotor retardation and vomiting. The patient fully recovered within 24 hours and conservative management was all that was required for treatment.
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 overdose, utilize general supportive measures.
There are currently no data on overdose with the rivastigmine transdermal system.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulfate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.
Contraindications
Hypersensitivity to rivastigmine, other carbamate derivatives (e.g. neostigmine, pyridostigmine, physostigmine) or any components of the formulation.
Special Precautions
GI effects: Rivastigmine is associated with clinically important adverse GI effects, including nausea and vomiting diarrhea, anorexia and weight loss., In controlled clinical trial, 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 recommend 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% 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 dosage and titration schedules, particularly when reinitiating therapy following temporary interruptions lasting longer than several days.
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 [NSAIDs] 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 secondary seizures 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 disease, including an increased incidence or intensity of tremor, reported.
Low weight Individuals: When rivastigmine transdermal system in 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.
Monitoring: Monitor patients closely for symptoms of active or occult GI bleeding, especially those at increased risk for developing ulcer (e.g. history of ulcer disease, concurrent NSAID use). Monitor patient for loss of appetite and/or weight loss.
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 treating clinical on a routine basis.
Use in Children: There are no adequate and well-controlled trials documenting the safety and efficacy of rivastigmine in any illness occurring in children.
Use in the Elderly: Age had no impact on the exposure to rivastigmine in patients with Alzheimer disease treated with the rivastigmine transdermal.
Use In Pregnancy & Lactation
Pregnancy: Category B. Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Should be used only if the benefit outweighs the potential risk to the fetus.
Lactation: Excretion in breast milk is unknown. The transdermal rivastigmine is not recommended in breast-feeding mother.
Adverse Reactions
>10%: Central nervous system: dizziness (2-21%), headache (3-17%).
Gastrointestinal: nausea (7-47%), vomiting (6-31%), diarrhea (5-19%), anorexia (3-17%), abdominal pain (1-13%).
1-10%: Cardiovascular: syncope (3%), hypertension (3%).
Central nervous system: fatigue (2-9%), insomnia (1-9%), confusion (8%), depression (4-6%), anxiety (2-5%), malaise (5%), somnolence (4-5%), hallucination (4%), aggressiveness (3%), parkinsonism symptoms worsening (2-3%), vertigo (≤2%).
Gastrointestinal: dyspepsia (9%), constipation (5%), flatulence (4%), weight loss (3-8%), eructation (2%), dehydration (2%).
Genitourinary: urinary tract infection (1-7%).
Neuromuscular and skeletal: weakness (2-6%), tremor (1%; up to 10% in parkinson's patients).
Respiratory: rhinitis (4%).
Miscellaneous: diaphoresis (4%), flu-like syndrome (3%).
<1% (limited to important or life-threatening symptoms; reaction may be at a similar frequency to placebo): abnormal hepatic function, acute renal failure, albuminurial, allergy, anemia, angina, aphasia, apnea, apraxia, atrial fibrillation, AV block, bradycardia, bronchospasm, bundle branch block, cachexia, cardiac arrest, cardiac failure, chest pain, cholecystitis, diplopia, diverticulitis, dysphagia, dysphonia, edema, esophagitis, extrasystoles, fecal incontinence, gastritis, gastroesophageal reflux, GGT increased, glaucoma, hematuria, hot flashes, hyper/hypoglycemia, hypercholesterolemia, hyper-/hypokinesia, hypertonia, hypokalemia, hyponatremia, hypotension, (including postural), hypothermia, hypothyroidism, intestinal obstruction, intracranial hemorrhage, mastitis, MI, migraine, neuralgia, palpitation, pancreatitis, paresthesia, periorbital or facial edema, peripheral ischemia, peripheral neuropathy, pneumonia, pruritus, psychiatric disorders, (e.g. Delirium, depersonalization, psychosis, emotional lability, suicidal ideation or tendencies), rash, respiratory depression, retinopathy, rigors, salivation, seizure, severe vomiting with esophageal rupture (following inappropriate reinitiation of of dose), sick sinus syndrome, Steven-Johnson syndrome, sudden cardiac death, supraventricular tachycardia, thrombocytopenia, thrombophlebitis, thrombosis, transient ischemia attack, ulcerative stomatitis, urinary incontinence, urticarial, and vasovagal syncope.
Drug Interactions
See Table.

Click on icon to see table/diagram/image
Storage
Store below 30°C.
Used systems should be folded, with the adhesive surfaces pressed together and discard safely.
Patient Counseling Information
To assure safe and effective use of rivastigmine transdermal, discuss this information and instructions provided as follows with patients.
1. Inform patients or caregivers of the importance of applying the correct dose on the correct part of their body. Also instruct them to rotate the application size in order to minimize skin irritation. The same site should not be used within 14 days. Instruct the patient to replace the transdermal patch every 24 hours at the same time every day. It may be helpful for this to be part of a daily routine, such as the daily bath or shower.
2. Avoid exposure of the transdermal patch to external heat sources (excess sunlight, saunas, solarium) for long periods of time.
3. Fold the transdermal patch in half after use and discard it in a place out of the reach and sight of children and pets. Also inform them that drug still remains in the transdermal patch after 24-hour use.
4. Avoid eye contact and to wash their hands after handling the transdermal patch.
5. While wearing the rivastigmine transdermal patch, the patient should not take rivastigmine capsules, rivastigmine oral solution or other drugs with cholinergic effects.
6. While wearing the rivastigmine transdermal patch, the potential GI adverse reactions such as diarrhea, nausea and vomiting may occur. Patients and caregivers should observe for these adverse reactions at all times and in particular when treatment is initiated or the dose is increased. Inform health care professionals if these adverse reactions persist, as a dose adjustment/reduction may be required.
7. Rivastigmine transdermal may affect the patient's appetite and/or the patient's weight. Any loss of appetite or weight reduction needs to be monitored.
8. If patients miss a dose, instruct them to apply a new transdermal immediately. They may apply the next transdermal patch at the usual time the next day. Advise patients not to apply 2 rivastigmine transdermal patches to make up for the one missed. If treatment has been missed for several days, inform patients or caregivers to restart treatment with the starting transdermal dose of 4.6 mg/24 hours. Titration to the next transdermal dose should proceed after 4 weeks.
ATC Classification
N06DA03 - rivastigmine ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Presentation/Packing
Transdermal patch 4.6 mg/24 hr [circular shaped transdermal system (TDS) with a diameter of approx. 2.4 cm; homogeneous, colourless to slightly yellowish and clear to slightly opaque adhesive layer and an on the outer side tan-coloured backing foil; mounted on an oversized transparent protective liner; printing on backing foil: "RIV-TDS 4.6 mg/24 h"] x 30's. 9.5 mg/24 hr [circular shaped transdermal system (TDS) with a diameter of approx. 3.4 cm; homogeneous, colourless to slightly yellowish and clear to slightly opaque adhesive layer and an on the outer side tan-coloured backing foil; mounted on an oversized transparent protective liner; printing on backing foil: "RIV-TDS 9.5 mg/24 h"] x 30's.
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