Mycofin may be available in the countries listed below.
Terbinafine hydrochloride (a derivative of Terbinafine) is reported as an ingredient of Mycofin in the following countries:
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Coxib may be available in the countries listed below.
Celecoxib is reported as an ingredient of Coxib in the following countries:
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Pyrazinamid Lederle may be available in the countries listed below.
Pyrazinamide is reported as an ingredient of Pyrazinamid Lederle in the following countries:
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In some countries, this medicine may only be approved for veterinary use.
In the US, Vancocin (vancomycin systemic) is a member of the drug class glycopeptide antibiotics and is used to treat Bacteremia, Bacterial Endocarditis Prevention, Bacterial Infection, Bone infection, Burns - External, Endocarditis, Enterocolitis, Febrile Neutropenia, Meningitis, Methicillin-Resistant Staphylococcus Aureus Infection, Nosocomial Pneumonia, Peritonitis, Pneumonia, Prevention of Perinatal Group B Streptococcal Disease, Pseudomembranous Colitis, Sepsis, Shunt Infection, Skin Infection and Surgical Prophylaxis.
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Vancomycin hydrochloride (a derivative of Vancomycin) is reported as an ingredient of Vancocin in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Hart may be available in the countries listed below.
Diltiazem hydrochloride (a derivative of Diltiazem) is reported as an ingredient of Hart in the following countries:
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Donepezil hydrochloride is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's disease.
Donepezil hydrochloride should be taken in the evening, just prior to retiring.
Donepezil hydrochloride can be taken with or without food.
The dosages of Donepezil hydrochloride shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.
The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of Donepezil hydrochloride might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
Donepezil hydrochloride has been shown to be effective in controlled clinical trials at a dose of 10 mg administered once daily.
The recommended starting dose of Donepezil hydrochloride is 5 mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5 mg dose. In open-label trials using a 6 week titration, the type and frequency of these same adverse events were similar between the 5 mg and 10 mg dose groups. Therefore, because Donepezil hydrochloride steady state is achieved about 15 days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
Donepezil hydrochloride is supplied as film-coated, round tablets containing 5 mg or10 mg of Donepezil hydrochloride.
The 5 mg tablets are blue, round, film-coated tablets, debossed with ‘HH205' on one side.
The 10 mg tablets are light yellow, round, film-coated tablets, debossed with ‘HH210'on the other side.
Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to Donepezil hydrochloride or to piperidine derivatives.
Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of Donepezil hydrochloride.
Donepezil hydrochloride, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose.
Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of Donepezil hydrochloride, patients should be observed closely at the initiation of treatment and after dose increases.
Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of Donepezil hydrochloride in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Although not observed in clinical trials of Donepezil hydrochloride, cholinomimetics may cause bladder outflow obstruction.
Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease.
Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
Mild to Moderate Alzheimer's Disease
Adverse Events Leading to Discontinuation
The rates of discontinuation from controlled clinical trials of Donepezil hydrochloride due to adverse events for the Donepezil hydrochloride 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from
5 mg/day to 10 mg/day was higher at 13%.
The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients are shown in Table 1.
| Dose Group | Placebo | 5 mg/day Donepezil Hydrochloride | 10 mg/day Donepezil Hydrochloride | |||
| Patients Randomized | 355 | 350 | 315 | |||
| Event/%Discontinuing | ||||||
| Nausea | 1% | 1% | 3% | |||
| Diarrhea | 0% | <1% | 3% | |||
| Vomiting | <1% | <1% | 2% | |||
Most Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride
The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by Donepezil hydrochloride's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued Donepezil hydrochloride treatment without the need for dose modification.
There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day.
See Table 2 for a comparison of the most common adverse events following one and six week titration regimens.
| No titration | One week titration | Six week titration | ||
| Adverse Event | Placebo (n=315) | 5 mg/day (n=311) | 10 mg/day (n=315) | 10 mg/day (n=269) |
| Nausea | 6% | 5% | 19% | 6% |
| Diarrhea | 5% | 8% | 15% | 9% |
| Insomnia | 6% | 6% | 14% | 6% |
| Fatigue | 3% | 4% | 8% | 3% |
| Vomiting | 3% | 3% | 8% | 5% |
| Muscle cramps | 2% | 6% | 8% | 3% |
| Anorexia | 2% | 3% | 7% | 3% |
Adverse Events Reported in Controlled Trials
The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received Donepezil hydrochloride and for which the rate of occurrence was greater for patients treated with Donepezil hydrochloride than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age.
| Body System/Adverse Event | Placebo (n=355) | Donepezil Hydrochloride (n=747) |
| Percent of Patients with any Adverse Event | 72 | 74 |
| Body as a Whole | ||
| Headache | 9 | 10 |
| Pain, various locations | 8 | 9 |
| Accident | 6 | 7 |
| Fatigue | 3 | 5 |
| Cardiovascular System | ||
| Syncope | 1 | 2 |
| Digestive System | ||
| Nausea | 6 | 11 |
| Diarrhea | 5 | 10 |
| Vomiting | 3 | 5 |
| Anorexia | 2 | 4 |
| Hemic and Lymphatic System | ||
| Ecchymosis | 3 | 4 |
| Metabolic and Nutritional Systems | ||
| Weight Decrease | 1 | 3 |
| Musculoskeletal System | ||
| Muscle Cramps | 2 | 6 |
| Arthritis | 1 | 2 |
| Nervous System | ||
| Insomnia | 6 | 9 |
| Dizziness | 6 | 8 |
| Depression | <1 | 3 |
| Abnormal Dreams | 0 | 3 |
| Somnolence | <1 | 2 |
| Urogenital System | ||
| Frequent Urination | 1 | 2 |
Other Adverse Events Observed During Clinical Trials
Donepezil hydrochloride has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1214 days.
Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving Donepezil hydrochloride. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.
Body as a Whole: Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness.
Cardiovascular System: Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis.
Digestive System: Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer.
Endocrine System: Infrequent: diabetes mellitus, goiter.
Hemic and Lymphatic System: Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.
Metabolic and Nutritional Disorders: Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.
Musculoskeletal System: Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation.
Nervous System: Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.
Respiratory System: Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.
Skin and Appendages: Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.
Special Senses: Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes.
Urogenital System: Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.
Severe Alzheimer's Disease
Adverse Events Leading to Discontinuation
The rates of discontinuation from controlled clinical trials of Donepezil hydrochloride due to adverse events for the Donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of Donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo) and urinary tract infection (2% vs. 1% placebo).
Most Frequent Adverse Events Seen in Association with the Use of Donepezil Hydrochloride
The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving Donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by Donepezil hydrochloride's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued Donepezil hydrochloride treatment without the need for dose modification.
Adverse Events Reported in Controlled Trials
Table 4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received Donepezil hydrochloride and for which the rate of occurrence was greater for patients treated with Donepezil hydrochloride than with placebo.
Body System/Adverse Event | Placebo (n=392) | Donepezil Hydrochloride (n=501) |
| Percent of Patients with any Adverse Event | 73 | 81 |
| Body as a Whole | ||
| Accident | 12 | 13 |
| Infection | 9 | 11 |
| Headache | 3 | 4 |
| Pain | 2 | 3 |
| Back Pain | 2 | 3 |
| Fever | 1 | 2 |
| Chest Pain | <1 | 2 |
| Cardiovascular System | ||
| Hypertension | 2 | 3 |
| Hemorrhage | 1 | 2 |
| Syncope | 1 | 2 |
| Digestive System | ||
| Diarrhea | 4 | 10 |
| Vomiting | 4 | 8 |
| Anorexia | 4 | 8 |
| Nausea | 2 | 6 |
| Hemic and Lymphatic System | ||
| Ecchymosis | 2 | 5 |
| Metabolic and Nutritional Systems | ||
| Creatine Phosphokinase Increased | 1 | 3 |
| Dehydration | 1 | 2 |
| Hyperlipemia | <1 | 2 |
| Nervous System | ||
| Insomnia | 4 | 5 |
| Hostility | 2 | 3 |
| Nervousness | 2 | 3 |
| Hallucinations | 1 | 3 |
| Somnolence | 1 | 2 |
| Dizziness | 1 | 2 |
| Depression | 1 | 2 |
| Confusion | 1 | 2 |
| Emotional Lability | 1 | 2 |
| Personality Disorder | 1 | 2 |
| Skin And Appendages | ||
| Eczema | 2 | 3 |
| Urogenital System | ||
| Urinary Incontinence | 1 | 2 |
Other Adverse Events Observed During Clinical Trials
Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer's disease during clinical trials of at least 6 months duration, including three double-blind placebo-controlled trials, two of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100 patients; Infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Donepezil hydrochloride treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies.
Body as a Whole: Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia.
Cardiovascular System: Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly.
Digestive System: Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage.
Endocrine System: Infrequent: diabetes mellitus.
Hemic and Lymphatic System: Frequent: anemia; Infrequent: leukocytosis.
Metabolic and Nutritional Disorders: Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased.
Musculoskeletal System: Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia.
Nervous System: Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia.
Respiratory System: Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma.
Skin and Appendages: Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash.
Special Senses: Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder.
Urogenital System: Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria.
Voluntary reports of adverse events temporally associated with Donepezil hydrochloride that have been received since market introduction that are not listed above, and for which there are inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.
No in vivo clinical trials have investigated the effect of Donepezil hydrochloride on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of Donepezil (164 nM), indicates little likelihood of interference.
Whether Donepezil hydrochloride has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of Donepezil hydrochloride for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of Donepezil hydrochloride on the pharmacokinetics of these drugs were observed.
Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit Donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.) increased mean Donepezil (5 mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of Donepezil hydrochloride.
Formal pharmacokinetic studies demonstrated that the metabolism of Donepezil hydrochloride is not significantly affected by concurrent administration of digoxin or cimetidine.
Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.
A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.
Pregnancy Category C: There are no adequate or well-controlled studies in pregnant women. Donepezil hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of Donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 16 times the maximum recommended human dose [MRHD] of 10 mg/day on a mg/m2 basis) and 10 mg/kg/day (approximately 20 times the MRHD on a mg/m2 basis), respectively. Oral administration of Donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose. The no-effect dose of 3 mg/kg/day is approximately 3 times the MRHD on a mg/m2 basis.
It is not known whether Donepezil is excreted in human breast milk. Caution should be exercised when Donepezil hydrochloride is administered to a nursing woman.
The safety and effectiveness of Donepezil hydrochloride in children have not been established.
Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with Donepezil hydrochloride was 73 years; 80% of these patients were between 65 and 84 years old, and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.
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 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. Tertiary anticholinergics such as atropine may be used as an antidote for Donepezil hydrochloride overdosage. Intravenous atropine sulfate 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).
Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature.
Donepezil hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl] methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.
Donepezil hydrochloride is available for oral administration in film-coated tablets containing 5, or 10 mg of Donepezil hydrochloride.
Inactive ingredients are lactose monohydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, corn starch, croscarmellose sodium. The film of 5 mg tablets coating contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, and FD&C blue. The 10 mg tablet contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, iron oxide yellow and iron oxide red.
Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission.
Donepezil hydrochloride is postulated 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 acetylcholinesterase. There is no evidence that Donepezil alters the course of the underlying dementing process.
Pharmacokinetics of Donepezil are linear over a dose range of 1-10 mg given once daily. The rate and extent of absorption of Donepezil hydrochloride tablets are not influenced by food.
The elimination half life of Donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 – 0.19 L/hr/kg. Following multiple dose administration, Donepezil accumulates in plasma by 4-7 fold, and steady state is reached within 15 days. The steady state volume of distribution is 12 - 16 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.
Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled Donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact Donepezil (53%) and as 6-O-desmethyl Donepezil (11%), which has been reported to inhibit AChE to the same extent as Donepezil in vitro and was found in plasma at concentrations equal to about 20% of Donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the Donepezil dose recovered in the urine as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance. These results suggest CYP2D6 has a minor role in the metabolism of Donepezil.
Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of Donepezil hydrochloride was decreased by 20% relative to 10 healthy age- and sex-matched subjects.
Renal Disease: In a study of 11 patients with moderate to severe renal impairment (ClC < 18 mL/min/1.73 m2) the clearance of Donepezil hydrochloride did not differ from 11 age- and sex-matched healthy subjects.
Age: No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of Donepezil hydrochloride. Population pharmacokinetic analysis suggested that the clearance of Donepezil in patients decreases with increasing age. When compared with 65-year old, subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year old subjects have a 33% in
Dagynil may be available in the countries listed below.
Estrogens, conjugated is reported as an ingredient of Dagynil in the following countries:
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