Reminisin

Donepezil hydrochloride.

REMINISIN 5: Each tablet contains Donepezil hydrochloride 5 mg.
REMINISIN 10: Each tablet contains Donepezil hydrochloride 10 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: Alzheimer's disease is characterized by cholinergic deficiency in the cortex and basal forebrain, which contributes to cognitive deficits. Donepezil reversibly and noncompetitively, inhibits centrally-active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system.
Pharmacokinetics: Absorption: Well absorbed.
Distribution: V_dss: 12 to 16 L/kg.
Protein binding: ~96%, primarily to albumin (75%) and alpha₁-acid glycoprotein (21%).
Metabolism: Extensive hepatic metabolism via CYP2D6 and 3A4 and glucuronidation to four major metabolites (two are active).
Half-life elimination: 70 hours.
Time to steady-state: 15 days.
Time to peak, plasma: Tablet, 10 mg: 3 hours.
Excretion: Urine 57% (17% as unchanged drug), feces (15%).

REMINISIN are indicated for the symptomatic treatment of: Mild, moderately severe and severe dementia of the Alzheimer's type; Vascular dementia (dementia associated with cerebrovascular disease); Dementia with Lewy bodies (DLB).

Recommended Dose: Adults/Elderly: Treatment is initiated at 5 mg/day (once-a-day dosing). REMINISIN should be taken orally, in the evening, just prior to retiring. The tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water, according to patient preference. The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil hydrochloride to be achieved. Following a 4-6 weeks of clinical assessment in patients who tolerated treatment at 5 mg/day, the dose of REMINISIN can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg for vascular dementia and DLB. Dose greater than 10 mg/day have not been studied in clinical trials for vascular dementia and DLB.
For patient with DLB, the dose may be decreased to 5 mg depending on the symptoms of the patient. Upon discontinuation of treatment, a gradual abatement of the beneficial effects of REMINISIN is seen. There is no evidence of a rebound effect after abrupt discontinuation of therapy.
Renal and hepatic impairment: A similar dose schedule can be followed for patients with renal impairment as clearance of donepezil hydrochloride is not affected by this condition. Due to possible increased exposure in mild to moderate hepatic impairment, dose escalation should be performed according to individual tolerability. There are no data for patients with severe hepatic impairment.
Children: REMINISIN is not recommended for use in children.
Mode of Administration: REMINISIN should be taken orally, in the evening, just prior to retiring. The tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water.

Overdose and Treatment: The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice and rats is 45 and 32 mg/kg, respectively, or approximately 225 and 160 times the maximum recommended human dose of 10 mg per day. Dose-related signs of cholinergic stimulation were observed in animals and included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsion, depressed respiration, salivation, miosis, fasciculation and lower body surface temperature.
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.
As in any case of overdose, general supportive measures should be utilized. Tertiary anticholinergics such as atropine may be used as an antidote for REMINISIN overdosage. Intravenous atropine sulphate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

REMINISIN is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.
REMINISIN is contraindicated in pregnancy.

Treatment should be initiated by a physician experienced in the treatment of dementia. Diagnosis should be made according to accepted guidelines (e.g. DSM IV, ICD 10). Therapy with donepezil should only be started if a care-giver is available who will regularly monitor drug intake for the patient. Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of donepezil should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutics effect is no longer present. Individual response to donepezil cannot be predicted.
Anaesthesia: REMINISIN, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.
Cardiovascular Conditions: Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on heart rate (e.g. bradycardia). The potential for this action may be particularly important to patients with "sick sinus syndrome" or other supraventricular cardiac conduction conditions, such as sinoatrial or atrioventricular block. There have been reports of syncope and seizures. In investigating such patients the possibility of heart block or long sinusal pauses should be considered.
Gastrointestinal Conditions: Patients at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms.
Genitourinary: Cholinomimetics may cause bladder outflow obstruction.
Neurological Conditions: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease. Cholinomimetics may have the potential to exacerbate or induce extrapyramidal symptoms.
Pulmonary Conditions: Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. The administration of REMINISIN concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergics system should be avoided
Severe Hepatic Impairment: There are no data for patients with severe hepatic impairment.
Effects on ability to drive and use machines: Donepezil has minor to moderate influence on the ability to drive and use machines. Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil can include fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil to continue driving or operating complex machines.

Pregnancy: Adverse events have been observed in some animal reproduction studies. For donepezil no clinical data on exposed pregnancies are available. REMINISIN should not be used during pregnancy.
Lactation: It is not known if donepezil is present in breast milk. The decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia.
The incidence profile for adverse events for severe Alzheimer's disease is similar to that of mild to moderately severe Alzheimer's disease. The table as follows reflects the incidence of adverse events in patients receiving treatment with REMINISIN for all stages of Alzheimer's disease.
Adverse reactions reported as more than an isolated case are listed as follows, by system organ class and by frequency. Frequencies are defined as very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100) and rare (>1/10,000, <1/1,000). (See table.)

Click on icon to see table/diagram/image

Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or, digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine. In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Drug interaction studies performed in vitro show that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%. Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta blocking agents which have effects on cardiac conduction.

Instruction for use: This drug should be prescribed by a neurologist, psychiatrist, or physician who takes care of patients in an elderly clinic.

Store below 30°C. Store in the aluminum pillow bag until taken.

Neurodegenerative Disease Drugs

N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.

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