Memry

Tablet: Memantine hydrochloride 10 mg Tablet is a white, oblong, biconvex, film-coated tablet, scored on both sides.
Each film-coated tablet contains: Memantine hydrochloride 10 mg.
Oral soln: 10 mg/mL Oral Solution: Clear, colorless to light yellowish oral solution. It comes with a pump which delivers 0.5 mL of the solution per actuation equivalent to 5 mg of memantine hydrochloride or 4.16 mg of memantine.
Each mL of oral solution contains: Memantine hydrochloride 10 mg.

Pharmacology: Tablet: Evidence suggests that malfunctioning of glutamatergic neurotransmission, particularly the N-methyl-D-aspartate (NMDA)-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine hydrochloride is a rapid, strongly voltage-dependent, low to moderate affinity uncompetitive (open-channel) NMDA-receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the Mg²⁺ ions voltage-dependent block of NMDA receptors and allow continuous influx of Ca²⁺ ions into cells which lead to neuronal degeneration. Studies showed that memantine hydrochloride binds more effectively than Mg²⁺ at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca²⁺ ions through the NMDA channels while preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus, memantine hydrochloride modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
There is no evidence that memantine hydrochloride prevents or slows neurodegeneration in patients with Alzheimer's disease. However, studies show that memantine hydrochloride produced statistically significant effects in preventing worsening in three endpoints (e.g., cognitive, global and functional) in patients with moderate to severe Alzheimer's disease (MMSE total score <20).
Memantine hydrochloride showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors and for voltage-­dependent Ca²⁺, Na⁺, K⁺ channels. Memantine hydrochloride also showed antagonistic effects at the 5HT₃ receptors with a potency similar to that for the NMDA receptors and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency. In vitro studies have shown that memantine hydrochloride does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine or tacrine.
Pharmacodynamics: Oral soln: The effects of glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), are mediated by various receptor types, including N-methyl-D-aspartate (NMDA) receptors, which play a role in physiologic processes such as learning and memory formation. The persistent activation of NMDA receptors by glutamate has been considered as a possible cause of neurodegeneration in different types of dementia, including dementia of the Alzheimer's type (Alzheimer's disease), and is thought to contribute to the symptomatology of Alzheimer's disease.
Memantine hydrochloride is a noncompetitive NMDA receptor antagonist. With low to moderate affinity, it preferentially binds to NMDA receptors-operated cation channels. Though not fully understood, memantine acts by effectively blocking glutamate under conditions of excessive stimulation. In addition, memantine exhibits antagonism at the type 3 serotonergic (5-HT) receptor with a potency that is similar to that at the 3NMDA receptor. Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth to that at the NMDA receptor. Memantine has low to negligible affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors, or for voltage dependent calcium, sodium, or potassium channels. In humans, memantine has not been shown to prevent or slow down the neurodegenerative processes, or alter the course of the underlying dementia process in patients with Alzheimer's disease.
Pharmacokinetics: Tablet: Memantine hydrochloride is completely absorbed after oral administration; absolute bioavailability is approximately 100%. It has linear pharmacokinetics over the therapeutic dose range of 10 to 40 mg. Maximum plasma concentration is achieved in 3 to 8 hours. Food tended to slow the rate but not the extent of memantine hydrochloride absorption.
Daily doses of 20 mg lead to steady-state plasma concentrations ranging from 70 to 150 ng/mL (0.5-1 µM) with large in interindividual variations. A mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was obtained when daily doses of 5 to 30 mg were administered. The volume of distribution is approximately 10 L/kg. Protein binding varied from 42 to 54% and no relationship was observed between plasma memantine hydrochloride concentration and protein binding.
Memantine hydrochloride undergoes partial hepatic metabolism. It is excreted mainly (60 to 80%) in its unchanged form in urine. Human metabolites are 1-amino-3-hydroxymethyl-5-methyl-adamantane, 3-amino-1-hyrdoxy-5,7-dimethyl-amantane and various secondary hydroxylated not yet definitively identified memantine hydrochloride derivatives; phase II metabolism amounts for up to 10%. The known metabolites do not have any NMDA-antagonistic activity. In vitro studies have shown that memantine hydrochloride is not metabolized by cytochrome P450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4.
Memantine hydrochloride is eliminated predominantly by the kidneys in a mono-exponential manner with a terminal half-life of 60 to 100 hours. In volunteers the normal kidney function, systemic clearance amounts to 170 mL/min. In a study on the absorption, metabolism and excretion of orally administered ¹⁴C-memantine, a mean of 84% of the dose was recovered within 20 days, the majority being excreted unchanged renally.
Renal clearance has been shown to depend on the pH of the urine. Under alkaline conditions, the renal clearance of unchanged memantine hydrochloride is markedly reduced compared to neutral or acidic urine conditions due to tubular reabsorption of memantine hydrochloride under alkaline conditions.
Special Population: Hepatic Impairment: After single oral dose administration of 20 mg memantine hydrochloride in subjects with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) and subjects who were age-, gender- and weight-matched to the hepatically-impaired subjects, no change in memantine hydrochloride exposure (based on C_max and AUC) was seen in subjects with moderate hepatic impairment as compared with healthy subjects. However, the terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects.
Renal Impairment: After single oral dose administration of 20 mg memantine hydrochloride in subjects with mild renal impairment (creatinine clearance, CL_cr, >50 to 80 mL), moderate renal impairment (Cl_cr 30 to 49 mL/min), severe renal impairment (CL_cr 5 to 29 mL/min), or in healthy subjects (Cl_cr 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment, the mean AUC_0-∞ increased by 4%, 60% or 115% in subjects with mild, moderate or severe renal impairment respectively, compared to healthy subjects. The terminal half-life increased by 18%, 41% or 95% in subjects with mild, moderate or severe renal impairment, respectively, compared to healthy subjects.
In the elderly with impaired renal function [creatinine clearance (CL_cr): 50 mL/min], a significant correlation was observed between CL_cr and total renal clearance (CL_tot) of memantine hydrochloride. Total renal clearance substantially exceeded renal clearance by filtration, thus indicating that a significant part of renal clearance is due to tubular secretion processes.
Oral soln: After oral administration, memantine is highly absorbed, with an absolute bioavailability of approximately 100%. Peak plasma concentrations (C_max) following single oral doses of the therapeutic range (i.e., 10 to 40 mg) of memantine were reached in about 3 to 8 hours after drug intake. Memantine has linear pharmacokinetics over the therapeutic dose range. Food tends to slow that rate of memantine absorption but not the extent of absorption. The administration of memantine 20 mg daily resulted to steady-state plasma concentrations ranging from 70 to 150 ng/mL with large interindividual variations.
The apparent volume of distribution of memantine is 9 to 11 L/kg, and the plasma protein binding is about 45%. Memantine rapidly crosses the blood-brain barrier, and a mean cerebrospinal fluid/serum ratio of 0.52 was attained with the daily administration of memantine 5 to 30 mg.
Memantine undergoes partial hepatic metabolism. In man, about 80% of the circulating memantine-related substance is present as the parent compound. The main metabolites of memantine in humans are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites demonstrate antagonism towards NMDA activity. The hepatic microsomal CYP450 enzyme is not significantly involved in the metabolism of memantine.
About 60% to 80% of the administered dose of memantine is excreted in the urine, predominantly in the unchanged form. Memantine is eliminated in a monoexponential manner, with a terminal elimination half-life of about 60 to 100 hours. Seventy-four percent (74%) of the administered dose is excreted as the sum of the parent drug and N-glucuronide conjugate. In subjects with normal kidney function, the total clearance of memantine is 170 mL/min/1.73 m. Renal clearance has been shown to involve the active tubular secretion regulated by pH-dependent tubular reabsorption and probably mediated by cation transport protein.
Special Populations: Renal impairment: The mean AUC from zero to infinity (AUC) increased by 4%, 60%, and 115% in patients with mild, moderate, and severe renal impairment, respectively. Compared to healthy subjects, the terminal elimination half-life increased by 18%, 41%, and 95% in patients with mild, moderate, and severe renal impairment, respectively.
A significant correlation between the creatinine clearance (CrCl) and total renal clearance of memantine was observed in elderly volunteers with impaired renal function (CrCl of 50 to ≤80 mL/min/1.73 m). After a single 20 mg oral dose of memantine, the systemic exposure in elderly patients with mild to moderate renal impairment were greater than elderly patients with normal renal functions by 14% and 39%, respectively. Total renal clearance was substantially higher than renal clearance by filtration, indicating that a significant part of renal clearance is due to tubular secretion.
Hepatic impairment: Memantine is metabolized to a minor extent into metabolites which do not possess NMDA antagonistic activity. The terminal elimination half-life of patients with moderate hepatic impairment (Child-Pugh B) was increased by about 16% compared to healthy subjects; memantine exposure was similar in healthy subjects, as measured by the C_max and AUC. The administration of memantine is not recommended in patients with severe hepatic impairment, as the pharmacokinetics of memantine have not been evaluated in this population.
Gender: After multiple dose administration of memantine 20 mg daily, females had about 45% higher exposure compared to males. However, there was no difference in exposure when body weight was considered.
Elderly: The pharmacokinetics of memantine in young and elderly patients are similar.

Tablet: Used in the treatment of moderate to severe Alzheimer's disease.
Oral soln: Symptomatic treatment of patients with moderate to severe Alzheimer's disease.

Tablet: Memantine hydrochloride can be taken with or without food.
Recommended Starting Dose: 5 mg once a day.
Recommended Maximum Dose: 20 mg per day.
The dose should be increased in 5 mg increments over the first four weeks of treatment reaching the recommended maintenance dose as follows: See Table 1.

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The minimum recommended interval between dose increase is one week.
Recommended Maintenance Dose: 20 mg per day.
Hepatic Impairment: In patients with mild or moderate hepatic impairment (Child-Pugh A and Child-Pugh B), no dosage adjustment is required. No data is available for patients with severe hepatic impairment. Administration of memantine is not recommended in patients with severe hepatic impairment.
Renal Impairment: Patients with mild renal impairment (CL_cr: 50 to 80 mL/min): No dosage adjustment is required in patients with mild renal impairment.
Patients with moderate renal impairment (CL_cr: 30 to 49 mL/min): 10 mg per day.
If well-tolerated after at least seven days of treatment, the dose can be increased up to 20 mg per day according to the standard titration scheme.
Patients with severe renal impairment (CL_cr: 5 to 29 mL/min): 10 mg per day.
Elderly (over 65 years old): 20 mg per day.
Or, as prescribed by a physician.
Oral soln: Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia. Diagnosis should be made according to current guidelines. It is recommended that treatment with memantine be initiated when a caregiver is available to regularly monitor patient's intake. The clinical benefit and the patient's tolerance should be reassessed, preferably within 3 months after start of treatment, and on a regular basis thereafter.
Treatment with memantine should be continued if favorable therapeutic benefit and tolerability are observed. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.
Memantine should be administered once per day and should be taken at the same time every day. If a dose is missed, the caregiver should be instructed to give the next dose to the patient as scheduled. There is no need to take the missed dose.
Memantine can be taken with or without food.
Recommended Oral Memantine Dose: Oral Solution: The maximum daily dose for adults is 20 mg daily. In order to reduce the risk of undesirable effects, the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows: See Table 2.

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Maintenance Dose: The recommended maintenance dose is 20 mg per day.
Special Populations: Renal Impairment: In patients with mildly impaired renal function (CrCl 50 to 80 mL/min), no dose adjustment is required. In patients with moderate renal impairment (CrCl 30 to 49 mL/min), daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg per day according to standard titration scheme.
In patients with severe renal impairment (CrCl of 5 to 29 mL/min), the maximum daily dose is 10 mg.
Hepatic Impairment: In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-to standard titration scheme adjustment is required. In patients with moderate renal impairment (CrCl 30 to 49 mL/min), daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg per day according impairment.
Children: The use of memantine in patients below 18 years old is not recommended.
Elderly (65 years and older): The recommended dose of memantine in elderly patients is 20 mg per day.

Tablet: Signs and symptoms associated with memantine hydrochloride overdosage include agitation, confusion, ECG changes, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness.
In one case of extreme overdosage, the patient survived the intake of up to 2,000 mg memantine hydrochloride showing CNS effects (e.g., coma, diplopia and agitation) which resolved without permanent sequela.
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, carte medicinalis (main ingredient is activated charcoal; 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.
Oral soln: There have been reported cases of accidental and intentional overdose with memantine. The highest ingested dose that has been reported in an overdose is 2,000 mg, which resulted to agitation, diplopia, and coma followed by a full recovery without permanent sequelae. Other signs and symptoms of overdose observed in clinical trials and postmarketing studies included asthenia, bradycardia, confusion, diarrhea, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, proconvulsiveness, psychosis, restlessness, slowed movement, somnolence, stupor, gait disturbance, visual hallucinations, vertigo, vomiting, and weakness. Fatal cases of overdoses were not reported during memantine monotherapy and only occurred when memantine was coadministered with several other drugs.
There is no specific antidote for memantine overdose. In the event of overdose, symptomatic and supportive treatment should be provided. An airway should be established and maintained to ensure adequate ventilation and oxygenation. Standard procedures to remove the active substance, such as gastric lavage, carbo medicinalis (the interruption of potential enterohepatic recirculation), forced diuresis, or the administration of activated charcoal should be considered. Cardiac and vital signs should also be monitored. Elimination of memantine can be enhanced by urine acidification.
Careful symptomatic clinical treatment should be considered in case of signs and symptoms of general CNS overstimulation.

Hypersensitivity to memantine hydrochloride or any ingredient of the product.
Oral soln: Or, as prescribed by a physician.

Tablet: Caution is recommended in patients with epilepsy, past history of convulsions or patients with predisposing factors for epilepsy.
Treatment with memantine hydrochloride should be initiated and supervised by a physician experienced in the diagnosis and treatment of dementia; diagnosis should be based on current guidelines. Therapy should be initiated only when a caregiver is available who will monitor patient compliance. Treatment with memantine hydrochloride should be continued only where there is a therapeutic benefit to the patient; therapeutic benefit should be reassessed on a regular basis.
The clearance of memantine hydrochloride was reduced by about 80% under alkaline urine conditions (pH 8). Thus, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Some factors that may raise urine pH may require careful patient monitoring. These factors include drastic changes in diet (e.g., from a carnivore to a vegetarian diet, or a massive ingestion of alkalizing gastric buffers), drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate) and the clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract with Proteus bacteria).
Moderate to severe Alzheimer's disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, memantine hydrochloride may change reactivity and therefore patients should be warned to take special care when driving a vehicle or operating heavy machinery.
Patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV) or uncontrolled hypertension were excluded in most clinical trials. As a result, only limited data are available and patients with these conditions should be closely supervised.
Ocular toxicity: Animal studies have shown adverse effects of memantine hydrochloride on the visual system. Dietary administration of memantine hydrochloride to rats for one year was associated with abnormal lysosomal storage in ganglion cells and retinal pigment cells at systemic exposures (plasma AUC) of 10-fold the anticipated clinical exposure at the recommended dose, while administration for eight weeks was associated with lens opacity, increased corneal and lens capsular densities, and histological changes in corneal and lens at exposures (plasma AUC) of 20-fold the clinical exposure. Oral administration of memantine hydrochloride to dogs with systemic exposures (plasma AUC) of 3- to 8-fold the clinical exposure was associated with corneal clouding/opacity and baboons showed swollen lenticular fibers in the eyes after oral memantine hydrochloride for three months at less than clinical exposure.
In a 6-month double-blind, placebo-controlled clinical study, specific ophthalmological examinations including slit lamp tests did not show any ocular changes. In the following 6-month open-label extension period, 368 patients underwent eye examinations. At the end of open label treatment, the incidence of cataract (lens previously clear but unclear at end of open label treatment) was reported in 11 of 197 patients (6%) treated with memantine hydrochloride for 12 months compared with 5 of 171 patients (3%) who received placebo in the double-blind period and then memantine hydrochloride for 6 months (p=0.3059).
Oral soln: Serious Hypersensitivity Reactions: Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) and other less serious skin reactions (e.g., erythema multiforme) have been rarely reported in patients receiving memantine. Patients or caregivers should be instructed to inform the physicians of any skin reactions that occur during treatment with memantine. Treatment should be discontinued at the first appearance of skin rash or any signs of a hypersensitivity reaction.
Neurological Conditions: The use of memantine has not been systematically evaluated in patients with seizure disorder. Seizure activity may be a manifestation of Alzheimer's disease. The risks and benefits of memantine treatment must epilepsy be carefully evaluated in patients with epilepsy, with a history of seizure disorder, or predisposing factors for Memantine should be administered with caution in these patients.
Genitourinary Conditions: Conditions that increase urinary pH by a factor of 7 to 9, such as drastic changes in diet (e.g., from a high-protein to a vegetarian diet), concurrent use of medications that alkalinize the urine [e.g., carbonic anhydrase inhibitors, sodium bicarbonate (see Interactions)], renal tubular acidosis, and severe urinary tract infections with Proteus bacteria, may reduce the elimination of memantine, resulting in increased plasma levels of the drug. Memantine should be used with caution in patients with these conditions. Careful monitoring is also recommended.
Cardiovascular Conditions: Since patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded in most clinical trials, patients with these conditions should be closely supervised during memantine therapy.
Low incidences of cardiovascular adverse events occurred during clinical trials in patients with moderate to severe Alzheimer's disease. However, increased frequencies of hypertension, angina, bradycardia, and cardiac failure adverse events were reported in patients treated with memantine compared to those treated with placebo. Caution should be observed when memantine treatment is initiated with cardiovascular conditions.
Ophthalmic Conditions: In an open-label study, the administration of memantine 20 mg daily in elderly patients for approximately 48 months resulted to threefold higher concentrations of the drug in the lacrimal fluid than in plasma; no ophthalmologic effects were seen. In another 6-month trial, worsening of the corneal condition was reported for slightly more patients administered with memantine than placebo.
Ocular changes were not seen with specific ophthalmological examinations, including slit lamp examinations, in a 6-month clinical study with memantine. In the following 6-month open label extension period of the study, the incidence of cataract (i.e., lens previously clear but unclear at end of open label treatment) was reported in 6% of patients treated with memantine for 12 months compared to 3% of patients who received placebo in the first 6 months and then memantine for the next 6 months.
Periodic monitoring for ophthalmic conditions is recommended during memantine therapy.
Use in patients with serious comorbidities: Since there is limited information on its safety when given to patients with moderate to severe Alzheimer's disease and serious comorbidities, careful risk/benefit assessment should be done prior to initiation. Dose escalation should be done with caution in this patient population.
Concomitant use with other drugs: The concomitant use of memantine with drugs chemically related to NMDA antagonists should be avoided, as this may result to more frequent or pronounced adverse drug reactions, particularly CNS-related adverse reactions (see Interactions).
Effects on Ability to Drive and Use Machines: Moderate to severe Alzheimer's disease usually impairs the driving performance and compromises the ability to use machines. In addition, memantine has minor or moderate influence on the ability to drive and use machines. Patients on memantine therapy should be warned to take special care in driving a vehicle or operating heavy machinery.
Use in Children: Tablet: There are no adequate and well-controlled studies on the efficacy and safety of memantine hydrochloride in any illness occurring in children.
Oral soln: The safety and effectiveness of memantine in pediatric patients have not been established. The use of memantine in children is not recommended. Women taking memantine should not breastfeed. The clinical need of the mother for memantine, together with the benefits of breastfeeding and the potential adverse effects of memantine to the breastfed infant, must also be considered.
Use in the Elderly: Oral soln: There were no clinically significant differences in most adverse events reported between patients ≥65 years old and younger adults. There is limited safety information on the use of memantine in patients ≥80 years old. The use of memantine in Alzheimer's patients with chronic comorbidities common among the elderly should only be considered after a proper benefit-risk assessment. In addition, the potential for compromised renal function in elderly patients should be considered when memantine is concomitantly used with other drugs eliminated through renal mechanism.

Tablet: Pregnancy Category B. There are no adequate and well-controlled studies of memantine hydrochloride in pregnant women. Memantine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether memantine hydrochloride is excreted in human milk. Caution should be exercised when memantine hydrochloride is administered to a breastfeeding mother.
Lactation: Oral soln: There are no data on the excretion of memantine in human breast milk, the effects on the breastfed infant, or the effects of memantine in milk production. However, the excretion of memantine in breast milk is possible due to its lipophilicity.

Tablet: Body as a whole: Fatigue, pain, leg pain, fall, pallor, malaise, inflicted injury, accidental injury, aggravated condition, hernia inguinal, hernia, congenital hernia, rigors, temperature change sensation, hypothermia, influenza-like symptoms, infection (bacterial, fungal), abrasion, cyst.
Cardiovascular: Hypertension, hypotension, postural hypotension, bradycardia, syncope, cardiac failure, angina pectoris, edema, peripheral edema, thrombophlebitis, atrial fibrillation, cardiac arrest, venous thrombosis/thromboembolism, hot flushes, pulse weak, cardiomegaly, ECG abnormal, heart disorder, heart murmur, aortic stenosis, arrhythmia (atrial and ventricular), bundle branch block, extrasystoles, heart block, palpitation; QT prolonged, rhythm & rate disturbance e.g., QTc prolongation, ischemic event, sudden death (e.g., myocardial infarction, tachycardia); aortic valve incompetence, coronary artery disorder, heart valve disorders, mitral insufficiency, transient ischemic attack, peripheral ischemia, thrombophlebitis, phlebitis, varicose vein, arteriosclerosis.
Nervous system: Dizziness, vertigo, headache, confusion, amnesia, insomnia, sleep disorder, somnolence, hallucination, agitation, nervousness, aggressive reaction, delusion, personality disorder, emotional lability, abnormal gait, depression, anxiety, psychosis, apathy, paranoid reaction, abnormal thinking, abnormal crying, paroniria, delirium, depersonalization, impaired concentration, excitation/mania, cerebrovascular accident, cerebral hemorrhage, ataxia, paresthesia, convulsions, extrapyramidal disorder, tardive dyskinesia, involuntary muscle contractions, hypertonia, tremor, hyporeflexia, paralysis, sensory disturbance, speech disorder, aphasia, hypoesthesia, abnormal coordination, abnormal reflexes, hemiplegia, hyperkinesia, hypokinesia, stupor, neuralgia, ischial neuralgia, ptosis, neuropathy, neurosis, suicide attempt, apraxia, cognitive disorders, convulsions, coma, encephalopathy, dementia, Alzheimer's disease.
Gastrointestinal: Dry mouth, toothache, tooth caries, tooth disorder, gingivitis, nausea, vomiting, diarrhea, dyspepsia, abdominal pain, gastroenteritis, diverticulitis, GI hemorrhage, esophageal ulceration, gastroesophageal reflux, esophagitis, dysphagia, eructation, flatulence, gastritis, GI neoplasm benign, ulcerative stomatitis, pancreatitis, constipation, change in bowel habits, colitis, diverliculosis, hemorrhage rectum, hemorrhoids, ileus, increased stool frequency, fecal incontinence, melena.
Hematologic: Anemia, leukopenia, basal cell and squamous carcinoma, malignant lymphoma, epistaxis, hematoma, hemorrhage, purpura, leukocytosis, erythrocyte sedimentation rate (ESR) increased, polycythemia, sepsis.
Respiratory: Coughing, dyspnea, bronchitis, upper respiratory tract infection, pneumonia, apnea, asthma, hemoptysis, rhinitis, pulmonary embolism, asthma, atelectasis, bronchospasm, chronic obstructive pulmonary disease, laryngitis, pharyngitis, pulmonary edema, respiratory disorder, respiratory insufficiency, sinusitis.
Musculoskeletal: Back pain, arthralgia, arthritis, arthrosis, bone disorder, bursitis, muscle weakness, myalgia, skeletal pain, involuntary muscle contractions, carpal tunnel syndrome.
Endocrine/Metabolic: Increased alkaline phosphatase, decreased weight, anorexia, appetite increased, dehydration, hypernatremia, hyponatremia, aggravated diabetes mellitus, hyperglycemia, hypoglycemia, osteoporosis, increased/decreased libido, impotence, antidiuretic hormone disorder, hyperthyroidism, hypothyroidism, thyroid stimulating hormone (TSH) increased, blood urea nitrogen (BUN) increased, gout, hypercholesterolemia, hyperkalemia, hypokalemia, hyperlipemia, hyperuricemia, non-protein nitrogen (NPN) increased, polydipsia.
Hepatic: Bilirubinemia, gamma-GT increased, hepatic enzymes increased, hepatic function abnormal, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased.
Reproductive/Urogenital: Urinary incontinence, urinary tract infection, frequent micturition, dysuria, polyuria, pyuria, renal calculus, renal cyst, abnormal renal function, hematuria, urinary retention, cystitis, benign and malignant breast neoplasm, moniliasis, vaginal hemorrhage.
Skin and appendages: Rash, skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria, abscess, herpes zoster, bullous eruption, dermatitis, hyperkeratosis, melanosis, onychomycosis, skin disorder, dry skin, skin exfoliation, skin reaction isolated, sweating increased, allergic reaction.
Special Senses: Cataract, conjunctivitis, macula lutea degeneration, decreased visual acuity, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival hemorrhage, eye pain, ectropion, retinal hemorrhage, xerophthalmia, diplopia, abnormal lacrimation, myopia, xerophthalmia, retinal detachment, decreased hearing, tinnitus, earache, ear disorder, otitis externa, taste perversion.
Oral soln: The most common adverse events associated with memantine include dizziness, confusion, headache, constipation, cough, hypertension, back pain, hallucination, pain, somnolence, vomiting, dyspnea, and fatigue.
Infections and infestations: Abscess, bacterial infection, bronchitis, candida infection, eye infection, fungal infection, infections, onychomycosis, sepsis, upper respiratory tract infection, urinary tract infection, viral infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma, benign gastrointestinal neoplasm, benign female breast neoplasm, carcinoma, cyst, malignant female breast neoplasm, lymphoma, malignant skin neoplasm, neoplasm, squamous cell carcinoma.
Blood and lymphatic system disorders: Agranulocytosis, anemia, epistaxis, leukocytosis, leukopenia, neutropenia, pancytopenia, polycythemia, thrombocytopenia, thrombotic thrombocytopenic purpura.
Immune system disorders: Bronchospasm, drug hypersensitivity, hypersensitivity, erythema multiforme.
Endocrine disorders: Antidiuretic hormone disorder, hyperthyroidism, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion.
Vascular disorders: Aggravated hypertension, aneurysm, aortic stenosis, arteriosclerosis, cerebral hemorrhage, cerebral infarction, cerebrovascular accident, claudication, deep vein thrombosis, embolism, flushing, hematoma, hemorrhage, hemorrhoids, hot flush, hypotension, orthostatic hypotension, ischemia, pallor, peripheral ischemia, phlebitis, syncope, thromboembolism, thrombophlebitis, transient ischemic attack, varicose vein, vascular disorder, venous thrombosis.
Gastrointestinal disorders: Abdominal pain, acute pancreatitis, change in bowel habits, colitis, dental caries, diarrhea, diverticulitis, diverticulosis, dry mouth, dysgeusia, dyspepsia, dysphagia, eructation, esophageal ulceration, esophagitis, fecal incontinence, flatulence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, ileus, inguinal hernia, melena, mouth ulceration, nausea, pancreatitis, rectal hemorrhage, saliva altered, salivary hypersecretion, toothache, tooth disorder.
Hepatic and hepatobiliary disorder: Cholelithiasis, hepatic failure, hepatitis (cholestatic, cytolytic), hyperbilirubinemia.
Cardiac disorders: Angina pectoris, arrhythmia, atrial fibrillation, atrioventricular block (complete, second-degree), bradycardia, bundle branch block, cardiac arrest, cardiac disorder, cardiac failure, cardiomegaly, chest pain (precordial), congestive heart failure, dependent edema, extrasystoles, heart block, left ventricular failure, myocardial infarction, palpitations, QTc prolongation, supraventricular arrhythmia, supraventricular tachycardia, tachycardia, torsades de pointes, ventricular arrhythmia.
Respiratory, thoracic, and mediastinal disorders: Apnea, aspiration pneumonia, asthma, atelectasis, choking, chronic obstructive airways disease, hemoptysis, influenza, laryngitis, pharyngitis, pneumonia, pulmonary edema, pulmonary embolism, rhinitis, respiratory disorder, respiratory insufficiency, sinusitis.
Reproductive system and breast disorders: Decreased libido, impotence, increased libido, menstrual disorder, prostatic disorder, vaginal hemorrhage.
Skin and subcutaneous tissue disorders: Abrasion, acne, acute generalized exanthematous pustulosis, alopecia, blister, bullous dermatitis, cellulitis, dermatitis, drug eruption, dry skin, ectropion, eczema, herpes zoster, hyperhidrosis, hyperkeratosis, localized skin reaction, melanosis, nevus, purpura, pemphigus, pruritus, rash (erythematous,) seborrhea, skin disorder, skin erosion, skin exfoliation, skin ulcer, Stevens-Johnson syndrome, toxic skin eruption, urticaria.
Renal and urinary disorders: Acute renal failure, cystitis, dysuria, hematuria, micturition disorder, micturition frequency, polyuria, pyuria, renal calculus, renal cyst, renal failure, renal insufficiency, urinary incontinence, urinary retention.
Musculoskeletal and connective tissue disorders: Aggravated arthritis, arthralgia, arthritis, bone disorder, bone pain, bursitis, chills, muscle contractions, muscular weakness, myalgia, osteoarthritis, osteoporosis, pain in extremity, rheumatoid arthritis, sciatica.
General disorders and administration site conditions: Asthenia, completed suicide, condition aggravated, fever, hernia, hypothermia, influenza-like illness, malaise, mucosal inflammation, neuroleptic malignant syndrome, sudden cardiac death, sudden death, temperature sensation changed.
Congenital, familial and genetic disorders: Congenital hernia, nevus.
Ear and labyrinth disorders: Decreased hearing, ear disorder, ear pain, otitis externa, otitis media, tinnitus.
Eye disorders: Abnormal lacrimation, abnormal vision, blepharitis, blurred vision, cataract, conjunctival hemorrhage, conjunctivitis, corneal opacity, decreased visual acuity, diplopia, eye disorder, eye pain, glaucoma, macula lutea degeneration, myopia, retinal detachment, retinal disorder, retinal hemorrhage, xerophthalmia.
Nervous system disorders: Abnormal coordination, abnormal reflexes, abnormal thinking, absence seizures, Alzheimer's disease, amnesia, aphasia, apraxia, ataxia, balance disorder, brain disease, carpal tunnel syndrome, cerebrovascular disorder, coma, convulsions, dementia, depressed level of consciousness, drug-induced Parkinson disease, dyskinesia, encephalopathy, extrapyramidal disorder, gait disturbance, grand mal convulsions, hemiparesis, hemiplegia, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, hyporeflexia, intracranial hemorrhage, involuntary muscle contractions, loss of consciousness, mental status change, myoclonus, neuralgia, paralysis, paresthesia, partial epileptic seizure, peripheral neuropathy, ptosis, restlessness, seizures, sensory disturbance, speech disorder, stupor, tardive dyskinesia, tremor, tonic-clonic seizures, vertigo.
Psychiatric disorders: Abnormal crying, agitation, aggression, anxiety, apathy, cognitive disorder, delirium, delusions, depersonalization, depression, disturbance in attention, emotional lability, insomnia, mania, nervousness, neurosis, nightmare, paranoia, personality disorder, psychotic disorders, sleep disorder, suicidal ideation, suicide attempt.
Metabolism and nutrition disorders: Aggravated diabetes mellitus, anorexia, dehydration, diabetes mellitus, edema, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hypernatremia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, increased appetite, peripheral edema, polydipsia, thirst.
Injury, poisoning and procedural complications: Accidental injury, bone fracture, fall, food poisoning, medication error, injury, procedure.
Investigations: Abnormal electrocardiogram (ECG), hepatic function, laboratory value, renal function; cardiac murmur; decreased weight; diagnostic procedures; increased alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, blood urea nitrogen, creatinine, erythrocyte sedimentation rate, gamma-glutamyl transpeptidase levels, International Normalized Ratio, liver function test, nonprotein nitrogen, thyroid stimulating hormone, weight; prolonged QT interval; weak pulse.
Surgical and medical procedures: Surgery.

Tablet: N-methyl-D-aspartate antagonists (amantadine, ketamine and dextromethorphan): Increased risk of CNS toxicity when memantine hydrochloride is given with NMDA antagonists. Avoid concomitant use. These compounds act at the same receptor system as memantine hydrochloride, and thus adverse drug reactions, mainly CNS-related, may be more frequent or more pronounced.
L-dopa, dopaminergic agonists (e.g., bromocriptine) and anticholinergics: The mode of action suggests that the effects of these drugs may be enhanced by concomitant treatment with NMDA-antagonists such as memantine hydrochloride.
Barbiturates and neuroleptics: The effects of these drugs may be reduced by memantine hydrochloride.
Antispasmodic agents (dantrolene or baclofen): Concomitant administration of memantine hydrochloride with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dosage adjustment may be necessary.
Oral anticoagulants (e.g., warfarin): Memantine hydrochloride possibly enhances the anticoagulant effect of warfarin. Close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants.
Cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine: May also possibly interact with memantine hydrochloride leading to a potential risk of increased plasma levels of both agents.
Diuretics [e.g., hydrochlorothiazide (HCTZ), triamterene (TA)]: There may be a possibility of reduced HCTZ plasma level when memantine hydrochloride is used concomitantly. However, co-administration of memantine hydrochloride and HCTZ/TA did not affect the bioavailability of either memantine hydrochloride or TA; the bioavailability of HCTZ is decreased by 20%.
Primidone: Memantine hydrochloride possibly reduces the effects of primidone.
Selegiline: Memantine hydrochloride possibly enhances the effects of selegiline.
Glibenclamide/metformin, donepezil and galantamine: No relevant drug-drug interaction.
Effects of memantine on substrates of microsomal enzymes: In vitro studies done with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine hydrochloride. Also, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine hydrochloride does not induce the cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Oral soln: NMDA Antagonists (e.g., amantadine, ketamine, dextromethorphan): Concomitant use of NMDA antagonists should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse drug reactions (e.g., CNS-related) may be more frequent or more pronounced. There is a risk of pharmacotoxic psychosis when memantine is given with amantadine, since these drugs are chemically related to NMDA antagonists.
Drugs affecting the CNS (e.g., L-dopa, dopaminergic agonists, anticholinergics, amantadine): The mode of action suggests that the effects of L-dopa, dopaminergic agonists (e.g., bromocriptine), and anticholinergics on the CNS may be potentiated with the coadministration of NMDA antagonists, including memantine.
The effects of barbiturates and neuroleptics may be diminished. The concurrent use of memantine with antispasmodic agents such as dantrolene or baclofen may modify their effects. Dose adjustments may be required if these drugs are to be coadministered with memantine. These recommendations are mainly based on theoretical information.
In vitro studies demonstrate that memantine does not affect the reversible acetylcholinesterase inhibition of donepezil, galantamine, or tacrine. The concomitant use of memantine with donepezil did not affect the pharmacokinetics of either drugs or alter substantially the acetylcholinesterase inhibition of donepezil.
Oral anticoagulants: Isolated cases of increased international normalized ratio (INR) have been reported in patients concomitantly treated with warfarin during postmarketing experience. Although causal relationship has not been established, close monitoring of prothrombin time or INR is recommended for patients receiving concomitant treatment with memantine and oral anticoagulants. Concurrent use of memantine and hydrochlorothiazide/triamterene did not affect bioavailability of either memantine or triamterene, and plasma concentrations and AUC of hydrochloride decreased by only 20%.
Alkalinizing agents (e.g., carbonic anhydrase inhibitors, sodium bicarbonate): Concomitant use of agents that increase urine pH may result to decreased clearance of memantine and lead to an accumulation of the drug and possible increase in adverse effects. At alkaline conditions (i.e., pH 8), the memantine clearance was decreased by approximately 80%. Caution must be observed when alkalinizing agents are coadministered with memantine. The pharmacokinetics of memantine is similar in smokers and non-smokers, suggesting that nicotine may not alter the pharmacokinetics of memantine.
Drugs using the same renal cationic transport system as amantadine (e.g., cimetidine, ranitidine, procainamide, quinidine, quinine, hydrochlorothiazide, triamterene, metformin, and nicotine): Altered plasma levels of both drugs is possible when memantine is coadministered with drugs secreted by the same renal cationic transport system as amantadine.
Highly protein bound drugs (e.g., warfarin, digoxin): As the protein binding of memantine is low (45%) interactions with highly protein bound drugs is unlikely.
Pregnancy: There are no adequate and well-controlled studies on the use of memantine in pregnant women. Memantine should not be given to pregnant women, unless clearly necessary and the expected benefits significantly outweighs the possible risks to the fetus. The serum level of hydrochlorothiazide may be reduced when memantine is concomitantly administered with hydrochlorothiazide or any combination with hydrochlorothiazide.
Immune system disorders: Bronchospasm, drug hypersensitivity, hypersensitivity, erythema multiforme.
Blood and lymphatic system disorders: Agranulocytosis, anemia, epistaxis, leukocytosis, leukopenia, neutropenia, pancytopenia, polycythemia, thrombocytopenia, thrombotic thrombocytopenic purpura.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma, benign gastrointestinal neoplasm, benign female breast neoplasm, carcinoma, cyst, malignant female breast neoplasm, lymphoma, malignant skin neoplasm, neoplasm, squamous cell carcinoma.
Infections and infestations: Abscess, bacterial infection, bronchitis, candida infection, eye infection, fungal infection, infections, onychomycosis, sepsis, upper respiratory tract infection, urinary tract infection, viral infection. The most common adverse events associated with memantine include dizziness, confusion, headache, constipation, cough, hypertension, back pain, hallucination, pain, somnolence, vomiting, dyspnea, and fatigue.
Acetylcholinesterase (AChE) inhibitors: In vitro studies demonstrated that memantine does not affect the reversible acetylcholinesterase inhibition by donepezil, tacrine, or galantamine. In young healthy adult subjects under steady-state conditions of donepezil, concurrent use with memantine did not alter the pharmacokinetics of either drug and did not affect donepezil-mediated AChE inhibition. A 24-week clinical study showed that in patients with moderate to severe Alzheimer's disease, the adverse event profiles were similar for patients treated with a combination of memantine and donepezil or placebo and donepezil.
The possibility of compromised renal function in elderly patients should be considered when memantine was concomitantly used with other drugs eliminated via renal mechanisms.
In single dose pharmacokinetic studies, no relevant interaction between memantine and glyburide/metformin was observed. The hypoglycemic effects of the glyburide/metformin combination were also not affected. The renal excretion of metformin and memantine should be considered when memantine and metformin will be used concomitantly.
Drugs metabolized by CYP enzymes: Due to its low extent of metabolism by CYP450 isoenzymes, metabolic drug interactions appear unlikely. In vitro studies revealed that memantine minimally inhibits CYP 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No induction of CYP 1A2, 2C9, 2E1, or 3A4/5 were observed in vitro at concentrations greater than those associated with clinical efficacy. Pharmacokinetic interactions with drugs metabolized by these enzymes are not expected. In a pharmacokinetics study in healthy adult subjects, memantine did not significantly affect the steady state pharmacokinetics of galantamine.
CYP Inhibitors and/or Inducers: Drugs that are substrates and/or inhibitors of the CYP450 system are unlikely to interact with memantine.
Atropine: Although serious interactions between very high doses of memantine and atropine have been noted in a toxicity study in rats, this interaction occurred under conditions not relevant to human treated at therapeutic doses of memantine.

Oral soln: Special Instructions: Instructions for proper use of the pump: The solution must not be poured directly into the mouth from the bottle or pump. Measure the dose onto a spoon or into a glass of water, using the pump.
Take the screw cap off the bottle: The cap must be turned counterclockwise, unscrewed completely and removed.
Slide the plastic dip tube carefully into the bottle. Hold the dosing pump onto the neck of the bottle and screw it clockwise until it its firmly. The dosing pump is only screwed on once when starting the use, and should never be unscrewed.
How the dosing pump works: The dosing pump head has two positions and is easy to turn: Counterclockwise to unlock and Clockwise to lock.
The dosing pump head should not be pushed down while in the locked position. The solution may only be dispensed in the unlocked position. To unlock, turn the pump head in the direction of the arrow (counterclockwise) until it cannot be turned any further (about one-eighth of a turn). The dosing pump is then ready to use.
Prepare the dosing pump: When used for the first time, the dosing pump does not dispense the correct amount of oral solution.
Therefore, the pump must be prepared (primed) by pushing the dosing pump head down completely five times in succession.
The solution dispensed is discarded. The next time the dosing pump head is pushed downwards completely (equivalent to one pump actuation), it dispenses the correct dose.
Correct use of the dosing pump: Hold a glass with a little water or a spoon below the nozzle. Slightly tilt the bottle, and push down the dosing pump head in a firm but calm and steady manner-not too slowly.
The dosing pump head can then be released and is ready for the next pump compression.
The dosing pump must only be used with the memantine solution in the bottle provided, not for other substances or containers.
If the pump does not function properly, consult a doctor or pharmacist.
Lock the closing pump after using memantine by turning the pump head clockwise.
Disposal: Do not throw away any medicines via wastewater or household waste. The dosing pump or pipette should be discarded in a place out of sight and reach of children.

Store at temperatures not exceeding 30°C.
Oral soln: Once opened, the contents of the bottle should be used within 12 weeks.
The bottle with the mounted pump must be kept and transported in an upright position.

Neurodegenerative Disease Drugs

N06DX01 - memantine ; Belongs to the class of other anti-dementia drugs.

Rx