DONECEPT-M/ DONECEPT-M FORTE Tablets (Donepezil hydrochloride + Memantine hydrochloride)

Table of Content

Composition

DONECEPT-M Tablets

Each film-coated tablet contains:

Donepezil Hydrochloride equivalent to Donepezil …………. 5 mg

Memantine Hydrochloride equivalent to Memantine ………….. 5 mg

DONECEPT-M FORTE Tablets

Each film-coated tablet contains:

Donepezil Hydrochloride equivalent to Donepezil ……………5 mg

Memantine Hydrochloride equivalent to Memantine ……………10 mg

Dosage Form

Film-coated tablet

Description

DONECEPT-M/DONECEPT-M FORTE is a fixed dose combination of donepezil hydrochloride and memantine hydrochloride.

Pharmacology

Pharmacodynamics

Donepezil Hydrochloride

Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase (AChE), the predominant cholinesterase in the brain. 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 AChE. Donepezil hydrochloride is, in vitro, over 1,000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system (CNS). There is no evidence that donepezil alters the course of the underlying dementing process.

Memantine Hydrochloride

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at N-methyl-D-aspartate (NMDA) receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia. Persistent activation of the CNS NMDA receptors by the excitatory amino acid, glutamate, has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low-to-moderate affinity, uncompetitive (open-channel) NMDA-receptor antagonist, which binds preferentially to the NMDA receptor-operated cation channels. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.

There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease. Memantine showed low-to-negligible affinity for Gama-Aminobutyric Acid (GABA), benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3-receptor with a potency similar to that for the NMDA-receptor and blocked nicotinic acetylcholine-receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of AChE by donepezil, galantamine or tacrine.

Pharmacokinetics

Absorption

Donepezil Hydrochloride

Donepezil is well absorbed, with a relative oral bioavailability of 100%. Peak 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 a gradual approach to the steady state. Approximate steady-state is achieved within 3 weeks after initiation of therapy. Once at the steady state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day. Food does not influence the rate or extent of absorption of donepezil hydrochloride.

Memantine Hydrochloride

Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.

Distribution

Donepezil Hydrochloride

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 to 1,000 ng/mL. The steady-state volume of distribution is 12 L/kg. The plasma protein binding of the active metabolite, 6-O-desmethyl-donepezil, is not known. Following multiple-dose administration, donepezil accumulates in plasma by 4- to 7-fold and the steady state is reached within 15 days. Though, the distribution of donepezil hydrochloride in various body tissues has not been definitively studied, in a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labelled 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.

Memantine Hydrochloride

The mean volume of distribution of memantine is 9 to 11 L/kg and the plasma protein binding is low (45%). Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70 to 150 ng/ml (0.5 to 1 µmol) with large inter-individual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated.

Metabolism

Donepezil Hydrochloride

Donepezil is 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 cytochrome (CY) P450 isoenzymes, 2D6 and 3A4, and undergoes glucuronidation.

Following administration of 14C-labelled 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, donepezil-cis-N-oxide (9%), 5-O-desmethyl-donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl-donepezil (3%). Approximately 57% and 15% of the total radioactivity was recovered in urine and faeces, 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. This suggests biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest entero-hepatic recirculation of donepezil hydrochloride and/or any of its metabolites.

Memantine Hydrochloride

In humans, about 80% of the circulating memantine-related material is present as the parent compound. Memantine undergoes partial hepatic metabolism. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites, which possess minimal NMDA-receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, more than 99% being excreted renally.

Elimination

Donepezil Hydrochloride

Donepezil hydrochloride is not only excreted in the urine intact but also metabolized by the CYP450 system to multiple metabolites, not all of which have been identified. The elimination half-life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 to 0.19 L/hr/kg.

Memantine Hydrochloride

Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption.

Memantine is eliminated in a mono-exponential manner, with a terminal T½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 ml/min/1.73 m² and part of total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular re-absorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7 to 9. Alkalization of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalizing gastric buffers.

Special Populations

Renal Impairment

Donepezil Hydrochloride

In a study of 11 patients with moderate-to-severe renal impairment (creatinine clearance <18 mL/min/1.73 m2), the clearance of donepezil did not differ from 11 age- and sex-matched healthy subjects.

Memantine Hydrochloride

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatine clearance, CLcr, >50 to 80 mL/min), 8 subjects with moderate renal impairment (CLcr, 30 to 49 mL/min), 7 subjects with severe renal impairment (CLcr, 5 to 29 mL/min) and 8 healthy subjects (CLcr >80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC (0–infinity) increased by 4%, 60% and 115% in subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. The terminal elimination half-life increased by 18%, 41% and 95% in subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment.

Hepatic Impairment

Donepezil Hydrochloride

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20% relative to 10 healthy age- and sex-matched subjects. Patients with mild-to-moderate hepatic impairment had increased donepezil steady-state concentrations, with mean AUC higher by 48% and mean Cmax by 39%.

Memantine Hydrochloride

Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) and 8 subjects who were age-, gender- and weight-matched to the hepatically impaired subjects. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine has not been evaluated in that population.

Age

Donepezil Hydrochloride

No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of donepezil. 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% increase in clearance. The effect of age on donepezil clearance may not be clinically significant.

Memantine Hydrochloride

The pharmacokinetics of memantine in young and elderly subjects are similar.

Gender, Race, and Smoking Habits

Donepezil Hydrochloride

No specific pharmacokinetic study was conducted to investigate the effects of gender, race, and smoking habits on the disposition of donepezil.

Memantine Hydrochloride

Following multiple-dose administration of memantine 20 mg b.i.d, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.

Indications

DONECEPT-M and DONECEPT-M FORTE Tablets are indicated for the symptomatic treatment of moderate-to-severe dementia of the Alzheimer's type.

Dosage and Administration

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia. Therapy should only be started if the caregiver is available who will regularly monitor drug intake by the patient.

Donepezil

The recommended starting dosage of donepezil is 5 mg administered once per day in the evening, just prior to retiring. 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. The maximum daily recommended dose should not exceed 10 mg of donepezil.

Memantine

The recommended starting dose of memantine is 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day, 15 mg/day, and 20 mg/day. The minimum recommended interval between dose increases is one week. The maximum recommended daily dose should not exceed 20 mg of memantine.

Dose of DONECEPT-M and DONECEPT-M FORTE should be individualized based on the efficacy and tolerability. DONECEPT-M and DONECEPT-M FORTE Tablets can be taken with or without food.

Contraindications

DONECEPT-M and DONECEPT-M FORTE Tablets are contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, memantine hydrochloride, piperidine derivatives or any of its excipients.

Warnings and Precautions

General

Anaesthesia

Donepezil, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia. Therefore, DONECEPT-M/DONECEPT-M FORTE Tablets should be used with caution during anaesthesia.

Cardiovascular Conditions

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. 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. In most clinical trials of memantine, patients with recent myocardial infarction, uncompensated congestive heart failure, or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised and DONECEPT-M/DONECEPT-M FORTE Tablets should be administered carefully.

Peptic Ulcer Disease and Gastrointestinal Bleeding and other Gastrointestinal Conditions

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 non-steroidal anti-inflammatory drugs (NSAIDS). Clinical studies of donepezil have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Donepezil, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhoea, nausea and vomiting. In most cases, these effects have been transient, sometimes lasting 1 to 3 weeks, and have resolved during continued use of donepezil. Patients should be monitored closely at the initiation of treatment with DONECEPT-M/DONECEPT-M FORTE Tablets and after the dose increases.

Genitourinary

Donepezil Hydrochloride

Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder outflow obstruction.

Memantine Hydrochloride

Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine.

Neurological Conditions

Seizures

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy. Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease. Cholinomimetics may have the potential to exacerbate or induce extra-pyramidal symptoms. Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.2% of patients treated with memantine and 0.5% of patients treated with placebo. Therefore, DONECEPT-M/DONECEPT-M FORTE Tablets should be used with caution in patients with neurological conditions.

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 DONECEPT-M/DONECEPT-M FORTE Tablets concomitantly with other inhibitors of AChE, agonists or antagonists of the cholinergic system should be avoided.

Weight Loss

Weight loss was reported as an adverse event in 2.5% of patients assigned to 10 mg/day of donepezil. Compared to their baseline weights, 4.9% of patients taking 10 mg/day of donepezil were found to have a weight loss of ≥7% at the end of the study.

Drug Interactions

Use of Donepezil with Anticholinergics

Because of the mechanism of action of donepezil, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.

Use with Cholinomimetics and Other AChE Inhibitors

A synergistic effect may be expected when cholinesterase inhibitors (donepezil) are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. Co-administration of memantine with the AChE inhibitor, donepezil hydrochloride, did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate-to-severe Alzheimer's disease, the adverse event profile observed with a combination of memantine and donepezil was similar to that of donepezil alone.

Effects of Memantine on Substrates of Microsomal Enzymes

In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4) flavin-containing monooxygenase, epoxide hydrolase or sulphation showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the CYP450 isozymes, CYP1A2, CYP2C9, CYP2E1 and CYP3A4/5.

Effect of Donepezil on the Metabolism of Other Drugs

No in vivo clinical trials have investigated the effect of donepezil on the clearance of drugs metabolized by CYP3A4 (e.g. cisapride, terfenadine) or by CYP2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50 to 130 μM), which, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. It is not known whether donepezil has any potential for enzyme induction. Formal pharmacokinetic studies evaluated the potential of donepezil for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of donepezil on the pharmacokinetics of these drugs were observed.

Effects of Other Drugs on the Metabolism of Donepezil

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 CYP2D6 and CYP3A4 (e.g. phenytoin, carbamazepine, dexamethasone, rifampin, phenobarbital and alcohol) could increase the rate of elimination of donepezil.

Formal pharmacokinetic studies demonstrated that the metabolism of donepezil is not significantly affected by concurrent administration of digoxin or cimetidine.

Effects of Inhibitors and/or Substrates of Microsomal Enzymes on Memantine

In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4) flavin-containing monooxygenase, epoxide hydrolase or sulphation showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the CYP450 isozymes, CYP1A2, CYP2C9, CYP2E1 and CYP3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the pharmacokinetics of memantine.

NMDA Antagonists

The combined use of memantine with other NMDA antagonists (amantadine, ketamine and dextromethorphan) has not been systematically evaluated and such use should be approached with caution. These drugs act at the same receptor system as memantine and, therefore, adverse drug reactions (mainly CNS-related) may be more frequent or more pronounced and, thus, use of DONECEPT-M/DONECEPT-M FORTE Tablets should be approached with caution.

Drugs Eliminated via Renal Mechanisms

Because memantine is eliminated in part by tubular secretion, co-administration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine and nicotine, could potentially result in altered plasma levels of both agents. However, co-administration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, co-administration of memantine with anti-hyperglycaemic drugs like glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of anti-hyperglycaemic drugs.

Drugs that Make the Urine Alkaline

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse reactions. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria. Hence, DONECEPT-M/DONECEPT-M FORTE Tablets should be used with caution under these conditions.

Renal Impairment

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction of DONECEPT-M/DONECEPT-M FORTE Tablets are recommended in patients with severe renal impairment.

Hepatic Impairment

There are no data for donepezil in patients with severe hepatic impairment. For memantine, no dosage adjustment is needed in patients with mild or moderate hepatic impairment. DONECEPT-M/DONECEPT-M FORTE Tablets should be administered with caution to patients with severe hepatic impairment.

Paediatric Use

There are no adequate and well-controlled trials to document the safety and efficacy of DONECEPT-M/DONECEPT-M FORTE Tablets in any illness occurring in children. DONECEPT-M/DONECEPT-M FORTE Tablets are not recommended for use in children.

Geriatric Use

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 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.

In the clinical studies of the combination of donepezil hydrochloride and memantine hydrochloride, the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old.

Pregnancy

There are no adequate or well-controlled studies in pregnant women. . Animal studies indicate a potential for reducing intrauterine growth at exposure levels, which are identical or slightly higher than at human exposure. DONECEPT-M/DONECEPT-M FORTE Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactation

It is not known whether donepezil or memantine is excreted in human breast milk. Taking into consideration the lipophilicity of memantine, it probably occurs. Women taking DONECEPT-M/DONECEPT-M FORTE Tablets should not breastfeed.

Undesirable Effects

Donepezil Hydrochloride

Adverse Reactions Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of donepezil due to adverse events for the donepezil 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 donepezil patients and at twice or more the incidence seen in placebo patients, are shown in Table 1.

Table 1: Most common adverse events leading to discontinuation in patients with mild to moderate Alzheimer’s disease

 

 

Adverse reactions

 

Placebo

(n=355)

%

5mg/day

Donepezil

(n=350)

%

10mg/day

Donepezil

(n=315)

%

Nausea

1

1

3

Diarrhoea

0

<1

3

Vomiting

<1

<1

2

Most Common Adverse Events

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 the cholinomimetic effects of donepezil. These include nausea, diarrhoea, insomnia, vomiting, muscle cramp, fatigue, ecchymosis and anorexia. These adverse events were often of mild intensity and transient, resolving during continued donepezil 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 1 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 1- and 6-week titration regimens.

Table 2: Comparison of rates of adverse events in mild-to-moderate patients titrated to 10 mg/day over 1 and 6 weeks

 

No titration

One week titration

Six week titration

Adverse reaction

Placebo

(n=315)

%

5mg/day

(n=311)

%

10mg/day

(n=315)

%

10mg/day

(n=269)

%

Nausea

6

5

19

6

Diarrhoea

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 treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received donepezil and for which the rate of occurrence was greater for patients treated with donepezil than with placebo were headache, pain (various locations), accident, fatigue, syncope, hypertension, haemorrhage, chest pain, nausea, diarrhoea, vomiting, anorexia, ecchymosis, weight decrease, muscle cramps, arthritis, insomnia, dizziness, depression, abnormal dreams, somnolence, frequent urination, fever, creatinine phosphokinase increased, dehydration, hyperlipidaemia, hostility, nervousness, hallucination, confusion, emotional liability, personality disorder, and eczema.

Other frequent adverse events reported were influenza, asthenia, fungal infection, chest pain, toothache, hypertension, vasodilation, bradycardia, atrial fibrillation, hot flashes, hypotension, faecal incontinence, gastrointestinal bleeding, bloating, epigastric pain, constipation, dyspepsia, dehydration, bone fracture, delusions, tremor, irritability, paraesthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia, dyspnoea, sore throat, bronchitis, pruritus, diaphoresis, urticaria, cataract, eye irritation, vision blurred, urinary incontinence, nocturia, haematuria, and glycosuria.

Other infrequent adverse events were oedema face, periorbital oedema, hernia hiatal, abscess, cellulitis, chills, generalized chill, head fullness, listlessness, sepsis, allergic reactions, cellulitis, angina pectoris, postural hypotension, myocardial infarction, AV-block (first degree), congestive heart failure, arteritis, peripheral vascular disease, supraventricular tachycardia, deep-vein thrombosis, cardiomegaly, supraventricular and ventricular extra-systole, eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue oedema, epigastric distress, gastroenteritis, increased transaminases, increased gamma-glutamyl transpeptidase, haemorrhoids, ileus, increased thirst, jaundice, melaena, polydipsia, duodenal ulcer, stomach ulcer, eructation, rectal haemorrhage, diabetes mellitus, goitre, anaemia, thrombocythaemia, thrombocytopenia, eosinophilia, erythrocytopenia, leucocytosis, gout, hypokalaemia, increased creatine kinase, hyperglycaemia, weight increase, increased lactate dehydrogenase, hypercholesterolaemia, BUN increased, hypoglycaemia, hyponatraemia, hypoproteinaemia, SGOT and SGPT increased, muscle weakness, muscle fasciculation, arthrosis, arthralgia, leg cramps, osteoporosis, myalgia, cerebrovascular accident, intracranial haemorrhage, transient ischaemic attack, emotional lability, apathy, euphoria, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing, vertigo, cerebrovascular accidents, increased salivation, ataxia, extra-pyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia, epistaxis, post-nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnoea, snoring, rhinitis, asthma, dermatitis, erythema, skin discolouration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer, dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal haemorrhage, otitis externa, otitis media, bad taste, conjunctival haemorrhage, ear buzzing, motion sickness, spots before eyes, dysuria, haematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis, and albuminuria.

Memantine Hydrochloride

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received doses of memantine up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the memantine group (10.1%) as in the placebo group (11.5%). No individual adverse event was associated with the discontinuation of treatment in 1% or more of memantine-treated patients and at a rate greater than placebo.

Adverse Events Reported in Controlled Trials

In double-blind placebo-controlled trials involving dementia patients, the most common adverse reactions (incidence ≥ 5% and higher than placebo) in patients treated with memantine were dizziness, headache, confusion and constipation.

Table 3 lists all adverse reactions that occurred in at least 2% of patients treated with memantine and at an incidence greater than placebo.

Table 3: Adverse reactions reported in controlled clinical trials in at least 2% of patients receiving combination of donepezil and memantine and at a higher frequency than placebo-treated patients

Adverse reaction

Placebo

N = 922

%

Memantine

N = 940

%

Body as a Whole

 

 

Fatigue

1

2

Pain

1

3

Cardiovascular system

 

 

Hypertension

2

4

Central and Peripheral Nervous system

 

 

Dizziness

5

7

Headache

3

6

Gastrointestinal system

 

 

Constipation

3

5

Vomiting

2

3

Musculoskeletal system

 

 

Back pain

2

3

Psychiatric Disorders

 

 

Confusion

5

6

Somnolence

2

3

Hallucination

2

3

Respiratory system

 

 

Coughing

3

4

Dyspnea

1

2

Other adverse events occurring with an incidence of at least 2% in memantine-treated patients but at a greater or equal rate on placebo were agitation, fall, inflicted injury, urinary incontinence, diarrhoea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, gait abnormal, depression, upper respiratory tract infection, anxiety, peripheral oedema, nausea, anorexia, and arthralgia.

The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate-to- severe Alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population.

Vital Sign Changes

Memantine and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight); and, (2) the incidence of patients meeting the criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with memantine. A comparison of supine and standing vital sign measures for memantine and placebo in elderly normal subjects indicated that memantine treatment is not associated with orthostatic changes.

ECG Changes

Memantine and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters; and, (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with memantine treatment.

Laboratory Changes

Memantine and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, haematology, and urinalysis variables; and, (2) the incidence of patients meeting the criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with memantine treatment.

Other frequently occurring adverse events reported in the clinical trials were syncope, cardiac failure, transient ischaemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia, anaemia, increased alkaline phosphatase, decreased weight, aggressive reaction, pneumonia, rash, cataract, conjunctivitis, and frequent micturition.

Other infrequently occurring adverse events were hypothermia, allergic reaction, angina pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary embolism, pulmonary oedema, paraesthesia, convulsions, extra-pyramidal disorder, hypertonia, tremor, aphasia, hypoaesthesia, abnormal coordination, hemiplegia, hyperkinesia, involuntary muscle contractions, stupor, cerebral haemorrhage, neuralgia, ptosis, neuropathy, gastroenteritis, diverticulitis, gastrointestinal haemorrhage, melaena, oesophageal ulceration, leucopenia, dehydration, hyponatraemia, aggravated diabetes mellitus, delusion, personality disorder, emotional lability, nervousness, sleep disorder, libido increased, psychosis, amnesia, apathy, paranoid reaction, thinking abnormal, crying abnormal, appetite increased, paroniria, delirium, depersonalization, neurosis, suicide attempt, apnoea, asthma, haemoptysis, skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticarial, macula lutea degeneration, decreased visual acuity, decreased hearing, tinnitus, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival haemorrhage, eye pain, retinal haemorrhage, xerophthalmia, diplopia, abnormal lacrimation, myopia, retinal detachment, dysuria, haematuria, and urinary retention.

Postmarketing Experience

The following adverse events have been identified during post-approval use of donepezil hydrochloride and memantine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes, acute renal failure, agranulocytosis, cardiac failure congestive, hepatitis, leukopenia (including neutropenia), pancreatitis, pancytopenia, Stevens Johnson Syndrome, suicidal ideation, thrombocytopenia, and thrombotic thrombocytopenic purpura.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024. 

Overdosage

Donepezil Hydrochloride

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 overdosage with donepezil hydrochloride. Intravenous atropine sulphate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg intravenous 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 and/or its metabolites can be removed by dialysis (haemodialysis, peritoneal dialysis or haemofiltration). 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.

Memantine Hydrochloride

Signs and symptoms associated with memantine overdosage in clinical trials and from worldwide marketing experience include agitation, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, diarrhoea, tiredness and weakness. The largest known ingestion of memantine worldwide was 2.0 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia and agitation, but subsequently recovered.

In the event of overdosage, treatment should be symptomatic. No specific antidote for intoxication or overdose is available. Standard clinical procedures to remove active substance material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, and forced diuresis should be used as appropriate. In case of signs and symptoms of general CNS overstimulation, careful symptomatic, clinical treatment should be considered. 

Incompatibility

None reported

Storage and Handling Instructions

Store in a cool, dry place, protected from light. Keep out of reach of children.

Packaging Information

DONECEPT-M Tablets............. Strip pack of 10 tablets

DONECEPT-M FORTE Tablets…………Strip pack of 10 tablets

 Last updated: October 2015

Last reviewed: February 2018