Tonizep FDT

Tonizep FDT

donepezil

Manufacturer:

T. O. Chemicals

Distributor:

T. O. Chemicals
Full Prescribing Info
Contents
Donepezil HCl.
Description
TONIZEP FDT 5: 5 mg donepezil hydrochloride tablets each containing 4.56 mg donepezil free base.
TONIZEP FDT 10: 10 mg donepezil hydrochloride tablets each containing 9.12 mg donepezil free base.
Action
Pharmacotherapeutic Group: Drugs for dementia. ATC Code: N06DA02.
Pharmacology: Pharmacodynamics: Donepezil hydrochloride is a specific inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. The drug binds reversibly with and inactivates cholinesterase, thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. Donepezil hydrochloride is in vitro over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system.
Alzheimer's dementia: Mild to moderately severe Alzheimer's disease: In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membrane) of 63.6% and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog, a sensitive scale which examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus donepezil hydrochloride cannot be considered to have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer's dementia with donepezil hydrochloride has been investigated in four placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.
In the 6-month clinical trial, an analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria: the ADAS-cog (a measure of cognitive performance), the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+ - a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (a measure of capabilities in community affairs, home and hobbies and personal care). (See Table 1.)
Patients who fulfilled the criteria listed below were considered treatment responders.
Response = Improvement of ADAS-cog of at least 4 points;
No deterioration of CIBIC+;
No deterioration of Activities of Daily Living Subscale of the Clinical; Dementia Rating Scale.

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Donepezil hydrochloride produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.
Severe Alzheimer's disease: Efficacy of treatment with donepezil hydrochloride in severe Alzheimer's disease has been investigated in three placebo-controlled trials of 6-month duration.
In each of the clinical trials, an analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria: the total Severe Impairment Battery (SIB - a measure of cognitive performance in all three trials) score, the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+ - a measure of global function in two trials) or Clinical Global Impression of Change (CGI-I - a measure of global function in one trial) and the modified Alzheimer's Disease Cooperative Study - Activities of Daily Living inventory for severe Alzheimer's disease (ADCS-ADL-sev - a measure of function in all three trials). (See Table 2.)
Patients who fulfilled the criteria listed below were considered treatment responders.
Response = Improvement of SIB at least 4 points;
No deterioration of CIBIC+ or CGI-I;
No deterioration of ADCS-ADL-sev.

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Vascular dementia: Efficacy of treatment of vascular dementia with donepezil hydrochloride has been investigated in three placebo-controlled trials of 6-month duration in which the diagnostic criteria for vascular dementia proposed by the NINDS-AIREN consensus group (National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences) were used to define the population of patients studied.
An overall analysis was done at the conclusion of donepezil hydrochloride treatment using a combination of three efficacy criteria. (See Table 3.)
Patients who fulfilled the criteria listed in Table 3 were considered treatment responders.
Response = Improvement of ADAS-cog of at least 4 points and;
Improvement or no deterioration of CIBIC+ and;
Improvement or no deterioration of Clinical Dementia Rating functionality subscale.

Click on icon to see table/diagram/image

Donepezil hydrochloride produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.
Pharmacokinetics: Absorption: Donepezil hydrochloride is well absorbed and food does not affect the absorption of the drug. Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 hours, thus, administration of multiple single-daily doses results in gradual approach to steady-state. Approximate steady-state is achieved within 3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride concentrations and the related pharmacodynamics activity show little variability over the course of the day.
Distribution: Donepezil hydrochloride is approximately 96% bound to human plasma proteins (to albumin approximately 75% and α1-acid glycoprotein approximately 21%). The plasma protein binding of the active metabolite 6-O-desmethyl donepezil is not known. The steady-state volume of distribution is 12 to 16 L/kg. In a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the label remained unrecovered. This suggests that donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.
Metabolism/Excretion: Donepezil hydrochloride is metabolized by the cytochrome P450 (CYP-450) isoenzymes 2D6 and 3A4 to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil), and 14.5% was recovered from the feces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.
Plasma donepezil hydrochloride concentrations decline with a half-life of approximately 70 hours and the mean apparent plasma clearance is 0.13 to 0.19 L/h/kg.
Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil hydrochloride has not been formally studied in healthy elderly subjects, or in Alzheimer's or vascular dementia patients. However, mean plasma levels in patients closely agreed with those of young healthy volunteers.
Patients with mild to moderate hepatic impairment had increased donepezil hydrochloride steady-state concentrations; mean AUC by 48% and mean Cmax by 39% (see Dosage & Administration).
Indications/Uses
TONIZEP FDT tablets are indicated for the symptomatic treatment of: Mild, moderate and severe Alzheimer's disease.
Vascular dementia (dementia associated with cerebrovascular disease) and dementia w/ Lewy bodies (DLB).
Dosage/Direction for Use
Recommended Dose: Adults/Elderly: Treatment is initiated at 5 mg/day (once-a-day dosing). The 5 mg/day dose should be maintained for at least one month in order 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 TONIZEP FDT can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Doses greater than 10 mg/day have not been studied in clinical trials.
Upon discontinuation of treatment, a gradual abatement of the beneficial effects of TONIZEP FDT 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 impairment as clearance of donepezil hydrochloride is not affected by this condition.
Due to possible increased exposure in mild to moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions), dose escalation should be performed according to individual tolerability. There are no data for patients with severe hepatic impairment.
Children: TONIZEP FDT is not recommended for use in children.
Mode of Administration: TONIZEP FDT 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.
Overdosage
The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice and rats in 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 convulsions, 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 donepezil hydrochloride 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 anti-cholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
Contraindications
TONIZEP FDT is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.
TONIZEP FDT is contraindicated in pregnancy.
Special Precautions
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 hydrochloride should only be started if a caregiver 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 hydrochloride should be reassessed on a regular basis. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Individual response to donepezil hydrochloride cannot be predicted. The use of donepezil hydrochloride in patients with other types of dementia or other types of memory impairment (e.g. amnestic mild cognitive impairment), is under investigation.
Anaesthesia: Donepezil hydrochloride, 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: Peptic ulcer/ GI bleeding: Patients at increased risk for developing ulcer or GI bleeding, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. However, the clinical studies with donepezil hydrochloride 5 to 10 mg/day showed no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Nausea/Vomiting: Donepezil hydrochloride, as a predictable consequence of its pharmacological properties, produced diarrhea, nausea, and vomiting. Although in most case, these effects were mild and transient, sometimes lasting 1 to 3 weeks, and resolved during continued use of donepezil hydrochloride, closely observe patients at the initiation of treatment and after dose increases.
Genitourinary: Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause bladder outflow obstruction.
Neurological conditions: Seizures: 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 donepezil hydrochloride concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided.
Severe hepatic impairment: There are no data for patients with severe hepatic impairment.
Effects on the Ability to Drive and Use Machines: Donepezil hydrochloride has minor to moderate influence in the ability to drive and use machines.
Dementia may cause impairment of driving performance or compromise the ability to use machinery. Furthermore, donepezil hydrochloride can induce fatigue, dizziness and muscle cramps, mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil hydrochloride to continue driving or operating complex machines.
Use In Pregnancy & Lactation
Use in Pregnancy: Category C according to US pregnancy category; either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
Teratology studies conducted in pregnant rats at doses up to approximately 80 times the human dose and in pregnant rabbits at doses up to approximately 50 times the human dose did not disclose any evidence for a teratogenic potential. However, in a study in which pregnant rats were given approximately 50 times the human dose from day 17 of gestation through day 20 postpartum, there was a slight increase in stillbirths and a slight decrease in pup survival through day 4 postpartum. No effect was observed at the next lower dose tested, approximately 15 times the human dose. Donepezil hydrochloride should not be used during pregnancy because no clinical data of it on exposed pregnancies are available.
Use in Lactation: It is not known whether donepezil hydrochloride is excreted in human breast milk and there are no studies in lactating women. Therefore, women on donepezil hydrochloride should not breast feed.
Adverse Reactions
The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting, anorexia, 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. Table 4 reflects the incidence of adverse events in patients receiving treatment with donepezil hydrochloride for all stages of Alzheimer's disease.
Adverse reactions reported as more than an isolated case are listed, 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 4.)

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Drug Interactions
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 hydrochloride. Drug interaction studies performed in vitro show that ketoconazole and guanidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil hydrochloride metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil hydrochloride. In a study in healthy volunteers, ketoconazole increased mean donepezil hydrochloride concentrations by about 30%. Moreover, CYP-450 3A4 and 2D6 inducers such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil hydrochloride. 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 such as atropine. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents, cholinergic agonists such as bethanechol, beta blocking agents which have effects on cardiac condition or aspirin/ NSAIDs such as ibuprofen, or naproxen may increase the risk of developing stomach ulcers.
Storage
Store in tight containers at temperatures below 30°C.
ATC Classification
N06DA02 - donepezil ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Presentation/Packing
Tonizep FDT 5: FD tab 5 mg (orodispersable, white, round with the figure "5" on one side and the letter "ZD" on the other side) x 2 x 14's.
Tonizep FDT 10: FD tab 10 mg (orodispersable, yellow, round with the figure "10" on one side and the letter "ZD" on the other side) x 2 x 14's, 10 x 2 x 14's.
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