Actions of Rivaldo in details
Pharmacology: Mechanism of Action: Pathological changes in dementia of Alzheimer type involve cholinergic pathways, which project from basal forebrain to the cerebral cortex and hippocampus. Though the exact mechanism of Rivaldo is unknown, it is postulated that it exert its therapeutic effect by enhancing cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. There is no evidence that Rivaldo alters the course of underlying dementing process. Following administration of 6 mg dose of Rivaldo, anticholinesterase activity is present in the CSF for 10 hrs, with maximum inhibition of about 60% 5 hrs after dosing.
Pharmacokinetics: Rivaldo is well absorbed with absolute bioavailability of about 40% (3 mg dose). Doubling of the dose from 3-6 mg twice daily results in a 3-fold increase in AUC. Peak plasma concentrations are reached in approximately 1 hr, but administration with food delays the absorption by 90 min.
Rivaldo is widely distributed through out the body with a volume of distribution in the range of 1.8-2.7 L/kg and readily crosses the blood brain barrier. About 40% of the drug is bound to plasma proteins, which cover the therapeutic range.
Rivaldo is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. Based on evidences from in vitro and animal studies, the major cytochrome P-450 isozymes are minimally involved in Rivaldo metabolism. Total plasma clearance of Rivaldo is approximately 130 L/hr after a 0.2 mg IV dose and decreased to 70 L/hr after a 2.7 mg IV dose.
The elimination half-life is about 1.5 hrs, with most elimination as metabolite in urine. The Cmax of Rivaldo was approximately 60% higher and the AUC was more than twice as high in subjects with mild to moderate hepatic impairment as compared to healthy subjects. There was no change in the Cmax and AUC of Rivaldo in subjects with severe renal impairment but they were more than twice as high in subjects with moderate renal impairment compared with healthy subjects.
Following a single oral dose of 2.5 mg, mean oral clearance of Rivaldo was 30% lower in elderly than in younger subjects.
How should I take Rivaldo?
Rivaldo is usually taken twice per day. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Take Rivaldo with food.
Rivaldo oral solution (liquid) comes with patient instructions for correctly measuring the dose. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.
You may swallow the liquid medicine directly from the syringe or mix the medicine with a small glass of water, fruit juice, or soda. Stir the mixture and drink all of it within 4 hours after mixing. To get the entire dose, add a little more water to the same glass, swirl gently and drink right away.
After using the syringe, wipe the outside of it with a clean tissue and put the syringe back into its protective case. Close the medicine bottle using the child resistant closure.
Use Rivaldo regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
Tell your doctor if you have any changes in weight. Rivaldo doses are based on weight, and any changes may affect the dose.
If you need surgery, tell the surgeon ahead of time that you are using Rivaldo. You may need to stop using the medicine for a short time.
If you stop taking Rivaldo for any reason, do not restart the medicine without talking to your doctor first. You may need to restart treatment with a lower dose.
Store Rivaldo at room temperature, away from moisture and heat. Do not allow the liquid medicine to freeze.
Rivaldo administration
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor.
Your doctor may occasionally change your dose to make sure you get the best results from this medication.
Rivaldo is usually taken twice a day, in the morning and evening. Follow your doctor's directions.
Take Rivaldo with food.
This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.
If you need to have any type of surgery, tell the surgeon ahead of time that you are taking Rivaldo. You may need to stop using the medicine for a short time.
Take the Rivaldo capsule with a full glass of water.
Do not use a regular table spoon to measure a dose of Rivaldo oral liquid (solution). Use the syringe provided.
You may swallow the oral liquid directly from the syringe or mix the medicine with a small glass of water, fruit juice, or soda. Do not use any other liquids to mix with Rivaldo oral liquid.
Stir the medicine mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.
After using the syringe, wipe the outside of it with a clean tissue and put the syringe back into its case. Close the medicine bottle using the child resistant closure.
It is important to use Rivaldo regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.
If you stop taking Rivaldo for any reason, do not restart the medication without talking to your doctor first. You may need to restart treatment with a lower dose.
Store Rivaldo at room temperature away from moisture and heat in an upright position.
Rivaldo pharmacology
Mechanism of Action
Although the precise mechanism of action of Rivaldo 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. The effect of Rivaldo may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that Rivaldo alters the course of the underlying dementing process.
Pharmacodynamics
After a 6-mg oral dose of Rivaldo in humans, anticholinesterase activity is present in cerebrospinal fluid 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 Rivaldo is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.
Pharmacokinetics
Absorption
After the initial application of Rivaldo transdermal system, there is a lag time of 0.5 to 1 hour in the absorption of Rivaldo. Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (Cmax) can also occur later (at 10 to 16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady state, trough levels are approximately 60% to 80% of peak levels.
Rivaldo transdermal system 9.5 mg/24 hours gave exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day). Inter-subject variability in exposure was lower (43% to 49%) for the Rivaldo transdermal system formulation as compared with the oral formulations (73% to 103%). Fluctuation (between Cmax and Cmin) is less for Rivaldo transdermal system than for the oral formulation of Rivaldo.
Figure 2 displays Rivaldo plasma concentrations over 24 hours for the 3 available patch strengths.
Figure 2: Rivaldo Plasma Concentrations Following Dermal 24-Hour Patch Application
Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system.
Exposure (AUC∞) to Rivaldo (and metabolite NAP266-90) was highest when the 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 the practitioner should be aware that the Rivaldo plasma exposure associated with these sites was approximately 20% to 30% lower.
There was no relevant accumulation of Rivaldo or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease with daily dosing.
The pharmacokinetic profile of Rivaldo transdermal patches was comparable in patients with Alzheimer’s disease and in patients with dementia associated with Parkinson’s disease.
Distribution
Rivaldo 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
Rivaldo is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in Rivaldo metabolism.
The metabolite-to-parent AUC∞ ratio was about 0.7 after Rivaldo transdermal system application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch 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.
Elimination
Renal excretion of the metabolites is the major route of elimination. Unchanged Rivaldo is found in trace amounts in the urine. Following administration of 14C-Rivaldo, renal elimination was rapid and essentially complete (>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 patch removal. Renal clearance was approximately 2.1 to 2.8 L/hr.
Age
Age had no impact on the exposure to Rivaldo in Alzheimer’s disease patients treated with Rivaldo transdermal system.
Gender and Race
No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Rivaldo transdermal system. A population pharmacokinetic analysis of oral Rivaldo 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. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Rivaldo transdermal system.
Body Weight
A relationship between drug exposure at steady state (Rivaldo and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Rivaldo exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the Rivaldo 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
No study was conducted with Rivaldo transdermal system in subjects with renal impairment. Based on population analysis creatinine clearance did not show any clear effect on steady state concentrations of Rivaldo or its metabolite.
Hepatic Impairment
No pharmacokinetic study was conducted with Rivaldo transdermal system in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of Rivaldo 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 Rivaldo 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 Rivaldo administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of Rivaldo by 23% (n=75 smokers and 549 nonsmokers).
Drug Interaction Studies
No specific interaction studies have been conducted with Rivaldo transdermal system. Information presented below is from studies with oral Rivaldo.
Effect of Rivaldo on the Metabolism of Other Drugs
Rivaldo 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 Rivaldo 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 Rivaldo.
Effect of Other Drugs on the Metabolism of Rivaldo
Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of Rivaldo.
Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of Rivaldo 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), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15).
References
- DailyMed. "RIVASTIGMINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- EPA DSStox. "Rivastigmine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Rivaldo are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Rivaldo. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
