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- MEMISTIN XR 14 MG MEMISTIN XR 28 MG Extended-Release Micro-Pellet Capsules Formula: One capsule contains 14 mg of memantine hydrochloride. One capsule contains 28 mg of memantine hydrochloride. Pharmacological Properties: Pharmacodynamic Properties: Mechanism of Action It is hypothesized that the persistent activation of N-methyl-D-aspartate (NMDA) receptors in the central nervous system by the excitatory amino acid glutamate contributes to the symptomatology of Alzheimer's disease. Memantine is believed to exert its therapeutic effect by acting as a noncompetitive (open-channel) NMDA receptor antagonist of low to moderate affinity, which preferentially binds to the cation channels of NMDA receptor-operated channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease. Pharmacodynamics Memantine has demonstrated low or negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histaminergic, and glycine receptors and for voltage-dependent Ca2+, Na+, or K+ channels. Memantine also exhibited 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 acetylcholinesterase by donepezil, galantamine, or tacrine. Pediatric Use The safety and efficacy of the drug in pediatric patients have not been established. Memantine failed to demonstrate efficacy in two 12-week controlled clinical trials involving 578 pediatric patients aged 6-12 years with autistic spectrum disorder (ASD), including autism, Asperger's disorder, and pervasive developmental disorder-not otherwise specified (PDD-Nos). Memantine has not been studied in pediatric patients younger than 6 years or older than 12 years. Treatment with memantine was initiated at a dose of 3 mg/day and the dose was titrated to the target dose (weight-based) by week 6. Oral doses of memantine 3 mg, 6 mg, 9 mg, or 15 mg extended-release capsules were administered once daily to patients weighing < 20 kg, 20-39 kg, 40-59 kg, and > 60 kg, respectively. In a randomized, 12-week double-blind, placebo-controlled parallel-group study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total score from baseline between memantine (n=54) and placebo (n=53) randomized patients. In a 12-week, responder-enriched randomized withdrawal study (Study B) involving 471 patients with autistic spectrum disorder, there was no statistically significant difference in the rate of loss of therapeutic response between patients randomized to remain on memantine at full dose (n=153) and patients randomized to switch to placebo (n=158). Pharmacokinetic Properties: Memantine is well absorbed after oral administration and exhibits linear pharmacokinetics over the therapeutic dose range. It is primarily excreted unchanged in the urine and has a terminal elimination half-life of approximately 60-80 hours. In a study comparing memantine XR 28 mg once daily to memantine 10 mg twice daily, Cmax and AUC0-24 values were 48% and 33% higher for the XR dosing regimen, respectively. Absorption Following multiple oral doses of memantine XR, the peak plasma concentration of memantine is achieved approximately 9-12 hours after dosing. No difference in the absorption of memantine XR was observed when the capsule was taken whole or if the contents were sprinkled on applesauce. There is no difference in the exposure to memantine, based on Cmax or AUC, for memantine XR, regardless of whether the drug was taken with or without food. However, peak plasma concentration is achieved approximately 18 hours after administration with food, compared to approximately 25 hours after administration when taken under fasting conditions. Distribution The mean volume of distribution of memantine is 9-11 L/kg, and plasma protein binding is low (45%). Elimination Metabolism Memantine undergoes partial metabolism in the liver. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine. Excretion Memantine is primarily excreted unchanged in the urine and has a terminal elimination half-life of approximately 60-80 hours. Approximately 48% of the administered dose is excreted unchanged in the urine; the remaining drug is primarily converted into three polar metabolites that possess minimal NMDA receptor antagonist activity: an N-glucuronide conjugate, 6-hydroxy-memantine, and 1-nitroso-deaminated memantine. 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion, which is modulated by pH-dependent tubular reabsorption. Special Populations Elderly The pharmacokinetics of memantine are similar in young and elderly subjects. Sex Following multiple daily doses of 20 mg memantine hydrochloride, exposure was 45% higher in women than in men, although no difference in exposure was observed after accounting for body weight. Renal Impairment The pharmacokinetics of memantine were studied after a single oral dose of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatinine clearance CLcr > 50-80 mL/min), 8 subjects with moderate renal impairment (creatinine clearance CLcr 30 - 49 mL/min), 7 subjects with severe renal impairment (creatinine clearance CLcr 5-29 mL/min), and 8 healthy subjects (CLcr > 80 mL/min) who were matched for age, weight, and sex to subjects with renal impairment. The mean AUC 0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. Hepatic Impairment The pharmacokinetics of memantine were evaluated following single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, 7-9 points) and 8 subjects matched for age, sex, and weight to subjects with hepatic impairment. No change in memantine exposure (by Cmax and AUC) was observed in subjects with moderate hepatic impairment compared to healthy volunteers. However, the terminal elimination half-life was increased by approximately 16% in subjects with moderate hepatic impairment compared to healthy subjects. Indications: MEMISTIN XR is indicated for the treatment of moderate to severe Alzheimer's type dementia. Contraindications: MEMISTIN XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or any of the excipients in this preparation. Warnings / Precautions: Conditions that increase urine pH can decrease the urinary excretion of memantine, leading to increased plasma levels of memantine (see section "Drug Interactions"). Fertility, Pregnancy, and Lactation: Pregnancy There are no adequate data on developmental risks associated with the use of memantine XR in pregnant women. Adverse effects on development (reduced body weight and skeletal ossification) were observed in offspring of rats treated with memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are high relative to the maximum recommended daily doses of memantine XR used in humans. The estimated background risk of major birth defects and miscarriage for the indicated populations are 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Animal Data Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) during the period of organogenesis in rats resulted in reduced fetal skeletal ossification at the highest tested dose. The higher no-effect dose for developmental toxicity (6 mg/kg) is 2 times the maximum recommended daily dose of memantine XR (28 mg) in humans (MRHD) on a body surface area basis (mg/m2). Oral administration of memantine (0, 3, 10, or 30 mg/kg/day) during the period of organogenesis in rabbits did not produce developmental toxicity. The maximum tested dose is approximately 20 times the MRHD of memantine XR on a mg/m2 basis. In rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally before mating and during the mating period, and in females during the period of organogenesis or throughout lactation until weaning. Reduced fetal skeletal ossification and reduced offspring weight were observed at the highest tested dose. The no-effect dose for developmental toxicity (6 mg/kg/day) is 2 times the MRHD of memantine XR on a mg/m2 basis. Oral dosing of memantine (0, 2, 6, or 18 mg/kg/day) in rats from late gestation through lactation until weaning resulted in reduced offspring weight at the highest tested dose. The no-effect dose (6 mg/kg/day) is approximately 2 times the MRHD of memantine XR on a mg/m2 basis. Lactation There is no information on the presence of memantine in human milk, the effects on the breastfed infant, or the effects on milk production. The benefits of breastfeeding along with the developmental and health benefits of breastfeeding should be considered along with the clinical need for MEMISTIN XR for the mother and any potential adverse effects on the breastfed infant from MEMISTIN XR or from the mother's underlying condition. Fertility No adverse effects on male or female fertility were observed with memantine. Effect on Ability to Drive and Use Machines: Moderate to severe Alzheimer's disease often impairs the ability to drive and use machines. Furthermore, memantine XR has a mild to moderate effect on the ability to drive and use machines. Therefore, ambulatory patients should be cautioned about taking special precautions. Adverse / Undesirable Effects: Memantine XR was studied in a double-blind placebo-controlled trial in which 676 patients with moderate to severe Alzheimer's type dementia were treated (341 patients with memantine XR 28 mg/day and 335 patients with placebo) for 24 weeks. Because clinical trials are conducted under widely varying conditions, the incidence rates of adverse events observed in the clinical trials of the drug cannot be directly compared to the incidence rates of adverse events in the clinical trials of another drug and may not reflect the incidence rates observed in practice. Adverse Events Leading to Treatment Discontinuation In the memantine XR placebo-controlled clinical trial, the proportion of patients in the memantine XR and placebo groups who discontinued treatment due to adverse events was 10% and 6%, respectively. The most frequent adverse event leading to treatment discontinuation in the memantine XR group was dizziness, at an incidence of 1.5%. Most Frequent Adverse Events in Patients Treated with Memantine XR The most frequently occurring adverse event in controlled clinical trials, with an incidence of at least 5% in the memantine XR group and a higher incidence than in the placebo group, was headache, diarrhea, and dizziness. Table 1. List of Adverse Events Reported with an Incidence of ≥2% in the Memantine XR Group and a Higher Incidence than in the Placebo Group. Adverse Event | Placebo (n=335) % | Memantine XR 28 mg (n=341) % ---|---|--- Gastrointestinal disorders | | Diarrhea | 4 | 5 Constipation | 1 | 3 Abdominal pain | 1 | 2 Vomiting | 1 | 2 Infections and infestations | | Influenza | 3 | 4 Investigations | | Weight increased | 1 | 3 Musculoskeletal and connective tissue disorders | | Back pain | 1 | 3 Nervous system disorders | | Headache | 5 | 6 Dizziness | 1 | 5 Somnolence | 1 | 3 Psychiatric disorders | | Anxiety | 3 | 4 Depression | 1 | 3 Aggression | 1 | 2 Renal and urinary disorders | | Urinary incontinence | 2 | 4 Vascular disorders | | Hypertension | 2 | 4 Hypotension | 1 | 2 Seizures Memantine has not been systematically evaluated in patients with seizure disorders. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo. Postmarketing Experience The following adverse events have been reported since the approval of memantine. Because these events 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. These adverse events include: Blood and lymphatic system disorders: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura. Cardiac disorders: congestive heart failure. Gastrointestinal disorders: pancreatitis. Hepatobiliary disorders: hepatitis. Psychiatric disorders: suicidal ideation. Renal and urinary disorders: acute renal failure (including elevated creatinine and renal failure). Skin disorders: Stevens-Johnson syndrome. In pediatric patients, the overall safety profile of memantine was generally consistent with the established safety profile in adults (see section "Adverse/Undesirable Effects"). In Study A, adverse events (n=56) in the memantine group that occurred in at least 5% of patients and at least twice the frequency of the placebo group (N=58) are presented in Table 2. Table 2: Study A - Frequently Reported Adverse Events with an Incidence of ≥ 5% and Twice the Frequency of the Placebo Group Adverse Event | Memantine N=56 % | Placebo N=58 % ---|---|--- Cough | 8.9% | 3.4% Influenza | 7.1% | 3.4% Rhinorrhea | 5.4% | 0% Excitement | 5.4% | 1.7% Aggression | 3.6% | 1.7% Irritability | 1.8% | 3.4% Adverse events that led to treatment discontinuation in more than one patient in any treatment group. Adverse events that occurred in at least 5% of patients in the 12-48 week open-label Study B to identify responders are listed in Table 3. Table 3: Study B 12-48 Week Open-Label Lead-in Study: Frequently Recorded Adverse Events with an Incidence of ≥ 5% Adverse Event | Memantine N=56 % ---|--- Headache | 8.0% Nasopharyngitis | 6.3% Hyperthermia | 5.8% Irritability | 5.4% Irritability | 1.2% Aggression | 1.0% Adverse events with an incidence of at least 1% that led to premature discontinuation of treatment. In the randomized withdrawal study (Study B), the adverse event that occurred in the placebo group (n=160) in randomized patients and was observed in at least 5% of patients and more than twice the rate of the full-dose memantine treatment group (n=157) was irritability (5.0% and 2.5%). In case of adverse events, consult your doctor for advice. Drug Interactions: Drugs that acidify the urine: Memantine clearance was reduced by approximately 80% under alkaline urine conditions at pH 8. Accordingly, a change in urine pH towards alkaline conditions may lead to accumulation of the drug with a possible increase in adverse effects. Urine pH can be altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), and the patient's clinical condition (e.g., renal tubular acidosis or severe urinary tract infections). Therefore, caution should be exercised when using memantine under these conditions. Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists The combined use of memantine XR with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and caution should be exercised when using them. Drug Interactions with Cholinesterase Inhibitors The use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either substance. Furthermore, memantine did not affect the inhibition of acetylcholinesterase by donepezil. In a 24-week controlled clinical trial in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with the combination of immediate-release memantine and donepezil was similar to that observed with donepezil monotherapy. Memantine's Effect on the Metabolism of Other Drugs In vitro studies conducted with CYP450 enzyme marker substrates (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. Furthermore, in vitro studies showed that at concentrations exceeding those associated with efficacy, memantine does not induce cytochrome P450 isoenzymes CYP1A2, -2C9, -2E1, and -3A4/5. Pharmacokinetic interactions with drugs metabolized by these enzymes are not expected. Pharmacokinetic studies have evaluated the potential for interaction between memantine and warfarin and bupropion. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion. Furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin, as assessed by prothrombin INR. Effect of Other Drugs on Memantine Memantine is primarily excreted by the kidneys, and drugs that are substrates and/or inhibitors of the CYP450 system are unlikely to alter the metabolism of memantine. Drugs Excreted by Renal Mechanisms Since memantine is partially excreted by tubular secretion, concomitant use of drugs that utilize the same cationic system in the kidney, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, may lead to altered plasma levels of both drugs. However, the coadministration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ was reduced by 20%. Furthermore, the coadministration of memantine with the antihyperglycemic agent Glucovance® (glyburide and metformin hydrochloride) did not alter the pharmacokinetics of memantine, metformin, and glyburide. Memantine also did not alter the hypoglycemic effect of Glucovance®, indicating a lack of pharmacodynamic interaction. Drugs Highly Bound to Plasma Proteins Since memantine has low plasma protein binding (45%), interactions with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, are unlikely. Dosage and Administration: Controlled clinical trials have shown that the effective dose of memantine XR is 28 mg once daily. The recommended starting dose of memantine XR is 7 mg once daily. The dose should be increased in increments of 7 mg to the recommended maintenance dose of 28 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum recommended dose is 28 mg daily. MEMISTIN XR may be taken with or without food. MEMISTIN XR capsules may be taken whole or may be opened, sprinkled on applesauce, and then swallowed. The entire contents of each MEMISTIN XR capsule must be taken; the dose cannot be divided. Unless the capsule is opened and sprinkled on applesauce as described above, MEMISTIN XR should be swallowed whole. MEMISTIN XR capsules should not be divided, chewed, or crushed. If a patient misses a dose of MEMISTIN XR, they should not double the next dose. The next dose should be taken as scheduled. If a patient misses several days of MEMISTIN XR, dosing should be restarted at a lower dose and then titrated as described above. Dose Titration Switching from Memantine to Memistin XR Capsules Patients being treated with memantine may be switched to memantine XR capsules as follows: It is recommended that a patient receiving 10 mg of memantine twice daily be switched to memantine XR 28 mg capsules once daily the day after the last dose of 10 mg memantine. There are no studies to support the comparative efficacy of these two regimens. In patients with severe renal impairment, it is recommended that a patient receiving 5 mg of memantine twice daily be switched to memistin XR 14 mg capsules once daily the day after the last dose of 5 mg memantine. Elderly The majority of elderly patients with Alzheimer's disease are 65 years of age and older. In the clinical study of extended-release memantine hydrochloride, the mean age of patients was approximately 77 years; over 91% were ≥ 65 years of age, 67% were ≥ 75 years of age, and 14% were ≥ 85 years of age. The efficacy and safety data presented in the clinical study were derived from these patients. No clinically significant differences in most adverse events were observed between patients ≥ 65 years of age and < 65 years of age. Renal Impairment In patients with severe renal impairment (creatinine clearance 5-29 mL/min, calculated by the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day (see section "Pharmacokinetic Properties"). Dose adjustment is not required in patients with mild or moderate renal impairment. Hepatic Impairment Dose adjustment is not required in patients with mild or moderate hepatic impairment. Memantine XR has not been studied in patients with severe hepatic impairment (see section "Pharmacokinetic Properties"). Pediatric Population Information is not available. Method of Administration MEMISTIN XR capsules are taken orally once daily, at the same time each day. The capsules may be taken with or without food. Overdosage: Based on clinical trials and worldwide marketing experience, signs and symptoms that commonly accompany overdosage with other forms of memantine, when used alone or in combination with other medicinal products and/or alcohol, include: excitement, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteadiness, visual hallucinations, vertigo, vomiting, and weakness. The largest reported dose of memantine worldwide was 2 grams in a patient who took memantine with unspecified antidiabetic drugs. The patient developed coma, diplopia, and excitement, but later recovered. One patient participating in a clinical trial of memantine XR accidentally took 112 mg of memantine XR daily for 31 days, and experienced elevated serum uric acid, elevated serum alkaline phosphatase, and decreased platelet count. Fatal outcome has been rarely reported with memantine and the association with memantine has not been established. As overdose management strategies are constantly evolving, it is advisable to contact a poison control center for information on the latest recommendations for the management of any drug overdose. As with any case of overdose, general supportive measures should be employed, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of the urine. Dispensing Category: Pharmaceutical Product Group II, dispensed by prescription form #3 Packaging Transparent PVC/PE/PVDC - Aluminum blister in a cardboard box. 28 Extended-Release Micro-Pellet Capsules / 2 blisters / 1 box (14 Extended-Release Micro-Pellet Capsules / 1 blister) Storage Conditions: The preparation should be stored at a temperature not exceeding 25°C, in its original packaging. Keep out of reach of children.
- Active
- memantine
What is it?
MEMISTIN XR 14 MG MEMISTIN XR 28 MG Extended-Release Micro-Pellet Capsules Formula: One capsule contains 14 mg of memantine hydrochloride. One capsule contains 28 mg of memantine hydrochloride. Pharmacological Properties: Pharmacodynamic Properties: Mechanism of Action It is hypothesized that the persistent activation of N-methyl-D-aspartate (NMDA) receptors in the central nervous system by the excitatory amino acid glutamate contributes to the symptomatology of Alzheimer's disease. Memantine is believed to exert its therapeutic effect by acting as a noncompetitive (open-channel) NMDA receptor antagonist of low to moderate affinity, which preferentially binds to the cation channels of NMDA receptor-operated channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease. Pharmacodynamics Memantine has demonstrated low or negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histaminergic, and glycine receptors and for voltage-dependent Ca2+, Na+, or K+ channels. Memantine also exhibited 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 acetylcholinesterase by donepezil, galantamine, or tacrine. Pediatric Use The safety and efficacy of the drug in pediatric patients have not been established. Memantine failed to demonstrate efficacy in two 12-week controlled clinical trials involving 578 pediatric patients aged 6-12 years with autistic spectrum disorder (ASD), including autism, Asperger's disorder, and pervasive developmental disorder-not otherwise specified (PDD-Nos). Memantine has not been studied in pediatric patients younger than 6 years or older than 12 years. Treatment with memantine was initiated at a dose of 3 mg/day and the dose was titrated to the target dose (weight-based) by week 6. Oral doses of memantine 3 mg, 6 mg, 9 mg, or 15 mg extended-release capsules were administered once daily to patients weighing < 20 kg, 20-39 kg, 40-59 kg, and > 60 kg, respectively. In a randomized, 12-week double-blind, placebo-controlled parallel-group study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total score from baseline between memantine (n=54) and placebo (n=53) randomized patients. In a 12-week, responder-enriched randomized withdrawal study (Study B) involving 471 patients with autistic spectrum disorder, there was no statistically significant difference in the rate of loss of therapeutic response between patients randomized to remain on memantine at full dose (n=153) and patients randomized to switch to placebo (n=158). Pharmacokinetic Properties: Memantine is well absorbed after oral administration and exhibits linear pharmacokinetics over the therapeutic dose range. It is primarily excreted unchanged in the urine and has a terminal elimination half-life of approximately 60-80 hours. In a study comparing memantine XR 28 mg once daily to memantine 10 mg twice daily, Cmax and AUC0-24 values were 48% and 33% higher for the XR dosing regimen, respectively. Absorption Following multiple oral doses of memantine XR, the peak plasma concentration of memantine is achieved approximately 9-12 hours after dosing. No difference in the absorption of memantine XR was observed when the capsule was taken whole or if the contents were sprinkled on applesauce. There is no difference in the exposure to memantine, based on Cmax or AUC, for memantine XR, regardless of whether the drug was taken with or without food. However, peak plasma concentration is achieved approximately 18 hours after administration with food, compared to approximately 25 hours after administration when taken under fasting conditions. Distribution The mean volume of distribution of memantine is 9-11 L/kg, and plasma protein binding is low (45%). Elimination Metabolism Memantine undergoes partial metabolism in the liver. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine. Excretion Memantine is primarily excreted unchanged in the urine and has a terminal elimination half-life of approximately 60-80 hours. Approximately 48% of the administered dose is excreted unchanged in the urine; the remaining drug is primarily converted into three polar metabolites that possess minimal NMDA receptor antagonist activity: an N-glucuronide conjugate, 6-hydroxy-memantine, and 1-nitroso-deaminated memantine. 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion, which is modulated by pH-dependent tubular reabsorption. Special Populations Elderly The pharmacokinetics of memantine are similar in young and elderly subjects. Sex Following multiple daily doses of 20 mg memantine hydrochloride, exposure was 45% higher in women than in men, although no difference in exposure was observed after accounting for body weight. Renal Impairment The pharmacokinetics of memantine were studied after a single oral dose of 20 mg memantine hydrochloride in 8 subjects with mild renal impairment (creatinine clearance CLcr > 50-80 mL/min), 8 subjects with moderate renal impairment (creatinine clearance CLcr 30 - 49 mL/min), 7 subjects with severe renal impairment (creatinine clearance CLcr 5-29 mL/min), and 8 healthy subjects (CLcr > 80 mL/min) who were matched for age, weight, and sex to subjects with renal impairment. The mean AUC 0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. Hepatic Impairment The pharmacokinetics of memantine were evaluated following single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, 7-9 points) and 8 subjects matched for age, sex, and weight to subjects with hepatic impairment. No change in memantine exposure (by Cmax and AUC) was observed in subjects with moderate hepatic impairment compared to healthy volunteers. However, the terminal elimination half-life was increased by approximately 16% in subjects with moderate hepatic impairment compared to healthy subjects. Indications: MEMISTIN XR is indicated for the treatment of moderate to severe Alzheimer's type dementia. Contraindications: MEMISTIN XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or any of the excipients in this preparation. Warnings / Precautions: Conditions that increase urine pH can decrease the urinary excretion of memantine, leading to increased plasma levels of memantine (see section "Drug Interactions"). Fertility, Pregnancy, and Lactation: Pregnancy There are no adequate data on developmental risks associated with the use of memantine XR in pregnant women. Adverse effects on development (reduced body weight and skeletal ossification) were observed in offspring of rats treated with memantine during pregnancy at doses associated with minimal maternal toxicity. These doses are high relative to the maximum recommended daily doses of memantine XR used in humans. The estimated background risk of major birth defects and miscarriage for the indicated populations are 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Animal Data Oral administration of memantine (0, 2, 6, or 18 mg/kg/day) during the period of organogenesis in rats resulted in reduced fetal skeletal ossification at the highest tested dose. The higher no-effect dose for developmental toxicity (6 mg/kg) is 2 times the maximum recommended daily dose of memantine XR (28 mg) in humans (MRHD) on a body surface area basis (mg/m2). Oral administration of memantine (0, 3, 10, or 30 mg/kg/day) during the period of organogenesis in rabbits did not produce developmental toxicity. The maximum tested dose is approximately 20 times the MRHD of memantine XR on a mg/m2 basis. In rats, memantine (0, 2, 6, or 18 mg/kg/day) was administered orally before mating and during the mating period, and in females during the period of organogenesis or throughout lactation until weaning. Reduced fetal skeletal ossification and reduced offspring weight were observed at the highest tested dose. The no-effect dose for developmental toxicity (6 mg/kg/day) is 2 times the MRHD of memantine XR on a mg/m2 basis. Oral dosing of memantine (0, 2, 6, or 18 mg/kg/day) in rats from late gestation through lactation until weaning resulted in reduced offspring weight at the highest tested dose. The no-effect dose (6 mg/kg/day) is approximately 2 times the MRHD of memantine XR on a mg/m2 basis. Lactation There is no information on the presence of memantine in human milk, the effects on the breastfed infant, or the effects on milk production. The benefits of breastfeeding along with the developmental and health benefits of breastfeeding should be considered along with the clinical need for MEMISTIN XR for the mother and any potential adverse effects on the breastfed infant from MEMISTIN XR or from the mother's underlying condition. Fertility No adverse effects on male or female fertility were observed with memantine. Effect on Ability to Drive and Use Machines: Moderate to severe Alzheimer's disease often impairs the ability to drive and use machines. Furthermore, memantine XR has a mild to moderate effect on the ability to drive and use machines. Therefore, ambulatory patients should be cautioned about taking special precautions. Adverse / Undesirable Effects: Memantine XR was studied in a double-blind placebo-controlled trial in which 676 patients with moderate to severe Alzheimer's type dementia were treated (341 patients with memantine XR 28 mg/day and 335 patients with placebo) for 24 weeks. Because clinical trials are conducted under widely varying conditions, the incidence rates of adverse events observed in the clinical trials of the drug cannot be directly compared to the incidence rates of adverse events in the clinical trials of another drug and may not reflect the incidence rates observed in practice. Adverse Events Leading to Treatment Discontinuation In the memantine XR placebo-controlled clinical trial, the proportion of patients in the memantine XR and placebo groups who discontinued treatment due to adverse events was 10% and 6%, respectively. The most frequent adverse event leading to treatment discontinuation in the memantine XR group was dizziness, at an incidence of 1.5%. Most Frequent Adverse Events in Patients Treated with Memantine XR The most frequently occurring adverse event in controlled clinical trials, with an incidence of at least 5% in the memantine XR group and a higher incidence than in the placebo group, was headache, diarrhea, and dizziness. Table 1. List of Adverse Events Reported with an Incidence of ≥2% in the Memantine XR Group and a Higher Incidence than in the Placebo Group. Adverse Event | Placebo (n=335) % | Memantine XR 28 mg (n=341) % ---|---|--- Gastrointestinal disorders | | Diarrhea | 4 | 5 Constipation | 1 | 3 Abdominal pain | 1 | 2 Vomiting | 1 | 2 Infections and infestations | | Influenza | 3 | 4 Investigations | | Weight increased | 1 | 3 Musculoskeletal and connective tissue disorders | | Back pain | 1 | 3 Nervous system disorders | | Headache | 5 | 6 Dizziness | 1 | 5 Somnolence | 1 | 3 Psychiatric disorders | | Anxiety | 3 | 4 Depression | 1 | 3 Aggression | 1 | 2 Renal and urinary disorders | | Urinary incontinence | 2 | 4 Vascular disorders | | Hypertension | 2 | 4 Hypotension | 1 | 2 Seizures Memantine has not been systematically evaluated in patients with seizure disorders. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo. Postmarketing Experience The following adverse events have been reported since the approval of memantine. Because these events 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. These adverse events include: Blood and lymphatic system disorders: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura. Cardiac disorders: congestive heart failure. Gastrointestinal disorders: pancreatitis. Hepatobiliary disorders: hepatitis. Psychiatric disorders: suicidal ideation. Renal and urinary disorders: acute renal failure (including elevated creatinine and renal failure). Skin disorders: Stevens-Johnson syndrome. In pediatric patients, the overall safety profile of memantine was generally consistent with the established safety profile in adults (see section "Adverse/Undesirable Effects"). In Study A, adverse events (n=56) in the memantine group that occurred in at least 5% of patients and at least twice the frequency of the placebo group (N=58) are presented in Table 2. Table 2: Study A - Frequently Reported Adverse Events with an Incidence of ≥ 5% and Twice the Frequency of the Placebo Group Adverse Event | Memantine N=56 % | Placebo N=58 % ---|---|--- Cough | 8.9% | 3.4% Influenza | 7.1% | 3.4% Rhinorrhea | 5.4% | 0% Excitement | 5.4% | 1.7% Aggression | 3.6% | 1.7% Irritability | 1.8% | 3.4% Adverse events that led to treatment discontinuation in more than one patient in any treatment group. Adverse events that occurred in at least 5% of patients in the 12-48 week open-label Study B to identify responders are listed in Table 3. Table 3: Study B 12-48 Week Open-Label Lead-in Study: Frequently Recorded Adverse Events with an Incidence of ≥ 5% Adverse Event | Memantine N=56 % ---|--- Headache | 8.0% Nasopharyngitis | 6.3% Hyperthermia | 5.8% Irritability | 5.4% Irritability | 1.2% Aggression | 1.0% Adverse events with an incidence of at least 1% that led to premature discontinuation of treatment. In the randomized withdrawal study (Study B), the adverse event that occurred in the placebo group (n=160) in randomized patients and was observed in at least 5% of patients and more than twice the rate of the full-dose memantine treatment group (n=157) was irritability (5.0% and 2.5%). In case of adverse events, consult your doctor for advice. Drug Interactions: Drugs that acidify the urine: Memantine clearance was reduced by approximately 80% under alkaline urine conditions at pH 8. Accordingly, a change in urine pH towards alkaline conditions may lead to accumulation of the drug with a possible increase in adverse effects. Urine pH can be altered by diet, drugs (e.g., carbonic anhydrase inhibitors, sodium bicarbonate), and the patient's clinical condition (e.g., renal tubular acidosis or severe urinary tract infections). Therefore, caution should be exercised when using memantine under these conditions. Concomitant use with other N-methyl-D-aspartate (NMDA) antagonists The combined use of memantine XR with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and caution should be exercised when using them. Drug Interactions with Cholinesterase Inhibitors The use of memantine with the acetylcholinesterase inhibitor donepezil did not affect the pharmacokinetics of either substance. Furthermore, memantine did not affect the inhibition of acetylcholinesterase by donepezil. In a 24-week controlled clinical trial in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with the combination of immediate-release memantine and donepezil was similar to that observed with donepezil monotherapy. Memantine's Effect on the Metabolism of Other Drugs In vitro studies conducted with CYP450 enzyme marker substrates (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. Furthermore, in vitro studies showed that at concentrations exceeding those associated with efficacy, memantine does not induce cytochrome P450 isoenzymes CYP1A2, -2C9, -2E1, and -3A4/5. Pharmacokinetic interactions with drugs metabolized by these enzymes are not expected. Pharmacokinetic studies have evaluated the potential for interaction between memantine and warfarin and bupropion. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion. Furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin, as assessed by prothrombin INR. Effect of Other Drugs on Memantine Memantine is primarily excreted by the kidneys, and drugs that are substrates and/or inhibitors of the CYP450 system are unlikely to alter the metabolism of memantine. Drugs Excreted by Renal Mechanisms Since memantine is partially excreted by tubular secretion, concomitant use of drugs that utilize the same cationic system in the kidney, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, may lead to altered plasma levels of both drugs. However, the coadministration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ was reduced by 20%. Furthermore, the coadministration of memantine with the antihyperglycemic agent Glucovance® (glyburide and metformin hydrochloride) did not alter the pharmacokinetics of memantine, metformin, and glyburide. Memantine also did not alter the hypoglycemic effect of Glucovance®, indicating a lack of pharmacodynamic interaction. Drugs Highly Bound to Plasma Proteins Since memantine has low plasma protein binding (45%), interactions with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, are unlikely. Dosage and Administration: Controlled clinical trials have shown that the effective dose of memantine XR is 28 mg once daily. The recommended starting dose of memantine XR is 7 mg once daily. The dose should be increased in increments of 7 mg to the recommended maintenance dose of 28 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum recommended dose is 28 mg daily. MEMISTIN XR may be taken with or without food. MEMISTIN XR capsules may be taken whole or may be opened, sprinkled on applesauce, and then swallowed. The entire contents of each MEMISTIN XR capsule must be taken; the dose cannot be divided. Unless the capsule is opened and sprinkled on applesauce as described above, MEMISTIN XR should be swallowed whole. MEMISTIN XR capsules should not be divided, chewed, or crushed. If a patient misses a dose of MEMISTIN XR, they should not double the next dose. The next dose should be taken as scheduled. If a patient misses several days of MEMISTIN XR, dosing should be restarted at a lower dose and then titrated as described above. Dose Titration Switching from Memantine to Memistin XR Capsules Patients being treated with memantine may be switched to memantine XR capsules as follows: It is recommended that a patient receiving 10 mg of memantine twice daily be switched to memantine XR 28 mg capsules once daily the day after the last dose of 10 mg memantine. There are no studies to support the comparative efficacy of these two regimens. In patients with severe renal impairment, it is recommended that a patient receiving 5 mg of memantine twice daily be switched to memistin XR 14 mg capsules once daily the day after the last dose of 5 mg memantine. Elderly The majority of elderly patients with Alzheimer's disease are 65 years of age and older. In the clinical study of extended-release memantine hydrochloride, the mean age of patients was approximately 77 years; over 91% were ≥ 65 years of age, 67% were ≥ 75 years of age, and 14% were ≥ 85 years of age. The efficacy and safety data presented in the clinical study were derived from these patients. No clinically significant differences in most adverse events were observed between patients ≥ 65 years of age and < 65 years of age. Renal Impairment In patients with severe renal impairment (creatinine clearance 5-29 mL/min, calculated by the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day (see section "Pharmacokinetic Properties"). Dose adjustment is not required in patients with mild or moderate renal impairment. Hepatic Impairment Dose adjustment is not required in patients with mild or moderate hepatic impairment. Memantine XR has not been studied in patients with severe hepatic impairment (see section "Pharmacokinetic Properties"). Pediatric Population Information is not available. Method of Administration MEMISTIN XR capsules are taken orally once daily, at the same time each day. The capsules may be taken with or without food. Overdosage: Based on clinical trials and worldwide marketing experience, signs and symptoms that commonly accompany overdosage with other forms of memantine, when used alone or in combination with other medicinal products and/or alcohol, include: excitement, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteadiness, visual hallucinations, vertigo, vomiting, and weakness. The largest reported dose of memantine worldwide was 2 grams in a patient who took memantine with unspecified antidiabetic drugs. The patient developed coma, diplopia, and excitement, but later recovered. One patient participating in a clinical trial of memantine XR accidentally took 112 mg of memantine XR daily for 31 days, and experienced elevated serum uric acid, elevated serum alkaline phosphatase, and decreased platelet count. Fatal outcome has been rarely reported with memantine and the association with memantine has not been established. As overdose management strategies are constantly evolving, it is advisable to contact a poison control center for information on the latest recommendations for the management of any drug overdose. As with any case of overdose, general supportive measures should be employed, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of the urine. Dispensing Category: Pharmaceutical Product Group II, dispensed by prescription form #3 Packaging Transparent PVC/PE/PVDC - Aluminum blister in a cardboard box. 28 Extended-Release Micro-Pellet Capsules / 2 blisters / 1 box (14 Extended-Release Micro-Pellet Capsules / 1 blister) Storage Conditions: The preparation should be stored at a temperature not exceeding 25°C, in its original packaging. Keep out of reach of children.