Approval Date.
Meperidine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Memantine Hydrochloride Tablets
English Name: Memantine Hydrochloride Tablets
Hanyu Pinyin：Yansuan Meijingang Pian
Ingredients
The main ingredient of this product is Memantine Hydrochloride.
Chemical name: 1-Amino-3,5-dimethyladamantaneamine hydrochloride
Chemical structure formula
Molecular formula: C12H21N-HCl
Molecular weight: 215.77
Excipients: microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, silicon dioxide, magnesium stearate, film-coated premix (gastric soluble type)
Characteristic】
This product is a light yellow to yellow, double-sided scarred oval film-coated tablets, after removing the coating appears white or off-white.
Indications
Treatment of moderately severe to severe Alzheimer’s type dementia.
Specification
10mg
Dosage and Administration
This product should be prescribed by a physician experienced in the diagnosis and treatment of Alzheimer’s type dementia and directed to the patient for use. Treatment should only be initiated if the patient has a caregiver who will supervise the patient’s medication on a regular basis. The diagnosis of dementia should be made in accordance with current diagnostic criteria and guidelines. The tolerability and dose of memantine should be repeatedly evaluated on some basis for three months from the start of treatment. Thereafter, the clinical benefit and patient tolerability of memantine should be re-evaluated on a basis consistent with current clinical guidelines. Once the benefit of treatment is clear and the patient can tolerate memantine therapy, maintenance therapy should be continued. If not, maintenance therapy with memantine should be discontinued.
This product should be taken once daily at the same time of day, either on an empty stomach or with food.
Adults: Maximum daily dose of 20 mg. To reduce the incidence of adverse reactions, the maintenance dose should be reached gradually in 5 mg weekly increments during the first 3 weeks of treatment as follows.
The dose for the first week of treatment is 5mg per day (half a tablet each time).
10mg daily (one tablet once daily) for the second week, and
15mg daily (one and a half tablets each time) in the third week.
The recommended maintenance dose of 20 mg per day (two tablets once daily) will be administered from the fourth week onwards.
Geriatric patients: Based on the results of clinical studies, the recommended dose for patients 65 years of age and older is 20 mg daily (two tablets once daily) (see [Geriatric Dosing]).
Pediatric and adolescent patients: Due to the lack of data on the safety and efficacy of this product for use in children and adolescents, it is not recommended for use in children and adolescents (see [Pediatric Dosage]).
Patients with renal insufficiency: In patients with mild renal insufficiency (creatinine clearance 50-80 ml/min), no dose adjustment is required. For patients with moderate renal insufficiency (creatinine clearance 30-49 ml/min), the dose of memantine should be reduced to 10 mg/day; if well tolerated after at least 7 days of treatment initiation, the dose may be increased to 20 mg/day according to the standard dose adjustment regimen. For patients with severe renal insufficiency (creatinine clearance 5-29 ml/min), the dose of memantine should be 10 mg/day.
Patients with hepatic insufficiency: No dose adjustment is required for patients with mild to moderate hepatic insufficiency (hepatic function class Child-Pugh A and Child-Pugh B). There is no information on the use of memantine in patients with severe hepatic insufficiency. This product is not recommended for use in patients with severe hepatic insufficiency.
[Adverse Reactions].
In clinical studies involving patients with moderately severe to severe Alzheimer’s type dementia, 1784 patients were included in the memantine treatment group and 1595 patients in the placebo group. The overall incidence of adverse events with this product was comparable to the placebo level, and the adverse events that occurred were usually mild to moderate. The common adverse reactions that occurred more frequently in patients taking memantine than in the placebo group were: dizziness (6.3% vs. 5.6%), headache (5.2% vs. 3.9%), constipation (4.6% vs. 2.6%), drowsiness (3.4% vs. 2.2%) and hypertension (4.1% vs. 2.8%).
The following table lists the cumulative adverse events observed in clinical studies since the first global launch of the product. In each group, adverse events are listed in descending order of severity.
The classification of adverse reactions by human organ system and incidence is as follows.
Very common (≥10%)
Common (≥1/100 and<1/10)
Rare (≥1/1,000 and <1/100)
Rare (≥1/10,000 and<1/1000)
Very rare (≤1/10,000)
Not known (could not be determined from available data)
Organ System Type Incidence Adverse Reactions Infections and Infectious Diseases Rare Fungal Infections Immune System Symptoms Common Drug Allergies Psychotic Symptoms Common Drowsiness Rare Confusion
Hallucinations1 Unknown psychotic reactions2 Neurological disorders common dizziness common balance disorders rare gait abnormalities very rare convulsions cardiovascular conditions rare heart failure vascular conditions common hypertension rare venous thrombosis/thrombosis respiratory organs, chest and mediastinum disorders common dyspnea gastrointestinal disorders common constipation rare vomiting unknown pancreatitis2 hepatobiliary disorders common elevated liver function test results unknown hepatitis systemic or local conditions Common headache Unknown fatigue1 Hallucinations are predominantly seen in patients with severe Alzheimer-type dementia.
2 Derived from post-marketing case reports.
Patients with Alzheimer-type dementia are often associated with depression and suicidal ideation and suicidal behavior, and such events have been reported after administration of this product.
Contraindications]
This product is contraindicated in patients with hypersensitivity to the active ingredient or its excipients.
Warnings and Precautions
Caution should be exercised when administering meperidine to patients with epilepsy, a history of convulsions or seizure susceptibility.
Combination with N-methyl-D-aspartate (NMDA) receptor antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These drugs act on the same receptor system as memantine and may increase the incidence of adverse drug reactions (primarily CNS-related) or lead to exacerbation of adverse reactions (see [Drug Interactions]).
Patients with elevated urinary pH must be closely monitored while taking this product. Factors that elevate urinary pH include abrupt changes in diet, such as a change from a meat-based diet to a vegetarian diet, or the administration of large amounts of alkaline gastric acid buffering solution. In addition, urinary pH may be elevated in patients with renal tubular acidosis (RTA) or severe urinary tract infections due to Aspergillus (see the “Elimination” section of [Pharmacokinetics]).
Because most clinical studies have not examined patients with recent myocardial infarction, non-compensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension, information on the use of memantine in these patients is limited and should be closely monitored while taking this product.
Moderately severe to severe Alzheimer’s disease usually results in impaired driving and mechanical operation, and memantine may have mild to moderate effects on patient responsiveness; therefore, patients taking this product should use special caution when driving or operating machinery.
Drug Interactions]
Depending on the pharmacological action and mechanism of action of this product, the following interactions may occur.
-The effects of levodopa, dopamine agonists and anticholinergic drugs may be enhanced when combined with NMDA antagonists; the effects of barbiturates and nerve blockers may be diminished. The effects of these drugs can be altered when memantine is combined with antitussive drugs such as dantrolene or baclofen, and therefore dose adjustment is required.
-Because memantine and amantadine are both NMDA antagonists in terms of chemical structure, they should be avoided in combination to avoid drug-induced psychosis. By the same token, memantine should not be combined with ketamine or dextromethorphan (see [Warnings and Precautions]). In one published case report, there was a possible increased risk of combining memantine with phenytoin.
-Because other drugs (e.g., cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine) share the same renal cation transport system as amantadine, there is also a potential risk of interaction with memantine, resulting in elevated plasma levels.
-Memantine has the potential to reduce serum levels of HCT when combined with dihydrocoumarotide (HCT) or any of the HCT-containing combination formulations.
-Post-marketing cases have been reported in which the combination of this product with Warfarin resulted in an increase in the International Normalized Ratio (INR). Although a causal relationship has not been established, close monitoring of clotting time or INR in patients with combined oral anticoagulants is required.
In a single-dose pharmacokinetic (PK) study in young healthy subjects, no interaction of memantine with eugenol/metformin or donepezil was observed.
A clinical study in young healthy subjects showed no effect of memantine on the pharmacokinetics of galantamine.
Memantine does not inhibit the activity of cytochrome enzymes (CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A), epoxide hydrolases and sulfation, and flavins containing monooxygenase under ex vivo conditions.
Pregnant women and nursing mothers
Pregnancy: There are no clinical data on the use of this product in pregnant patients. Animal studies have shown that administration of meperidine at doses equal to or slightly higher than those used in humans may result in intrauterine fetal growth retardation (see [Pharmacology and Toxicology]). The potential risk to humans is not known. This product should not be taken during pregnancy unless clearly needed.
Lactation: It is not clear whether memantine can be secreted from breast milk, but given the lipophilic nature of memantine, this possibility exists. Therefore, nursing women should stop breastfeeding while taking this product.
For Children
There is no information on the efficacy and safety of this product for use in children and adolescents.
Geriatric use]
The recommended dose for patients over 65 years of age is 20mg per day (two tablets once daily).
Drug Overdose】
There is limited experience with drug overdose from clinical studies and post-marketing experience.
Symptoms: Larger overdose (200 mg and 105 mg/day for 3 days, respectively) with any of the following symptoms: fatigue, weakness and/or diarrhea or no symptoms. Central nervous system (confusion, drowsiness, somnolence, dizziness, euphoria, aggressive behavior, hallucinations, and gait abnormalities) and/or gastrointestinal reactions (vomiting and diarrhea) in patients taking less than 140 mg or at an unknown dose.
In the most extreme case of overdose, the patient had a CNS reaction (coma for 10 days, followed by diplopia and euphoria) after taking a total of 2000 mg of memantine. The patient was treated with symptomatic therapy and plasma removal. The patient was cured without permanent sequelae.
Another patient with a severe drug overdose also survived and was cured. The patient received up to 400 mg of meperidine orally and experienced post-dose CNS reactions (including restlessness, psychotic symptoms, visual hallucinations, pre-convulsions, drowsiness, miosis, and impaired consciousness).
Treatment: Symptomatic treatment. There is no specific antidote for poisoning or drug overdose. Standard clinical procedures include removal of active ingredients, such as gastric lavage, activated charcoal (to prevent potential enterohepatic circulation), urinary acidification function, and forced diuresis if necessary.
If signs and symptoms of systemic central nervous system (CNS) overstimulation are present, careful symptomatic treatment should be considered.
Clinical Pharmacology]
Pharmacokinetics
The absolute bioavailability of memantine is about 100% with a Tmax of 3-8 hours. Food does not affect the absorption of memantine. The pharmacokinetics are linear in the dose range of 10-40 mg. Steady-state plasma concentrations of memantine at a daily dose of 20 mg ranged from 70-150 ng/ml (0.5-1 mmol), with large individual differences. The mean cerebrospinal fluid (CSF)/serum ratio after daily administration of 5-30 mg of memantine was 0.52. The volume of distribution was approximately 10 L/kg. The plasma protein binding rate was 45%.
In the human body, approximately 80% exists in its native form. The major metabolites in humans are N-3,5-dimethyl-glucuronide, a mixture of isomers of 4-hydroxymevalonate and 6-hydroxymevalonate, and 1-nitroso-3,5-dimethyl-adamantanamine. None of these metabolites exhibited NMDA antagonistic activity. The product was not found to be metabolized by the cytochrome P450 enzyme system in ex vivo experiments.
In an oral 14C-mevalonate study, an average of 84% of the product was excreted within 20 days and more than 99% was excreted renally.
The elimination half-life of this product was t½ 60-100 hours. In volunteers with normal renal function, the overall clearance (Cltot) was 170 ml/min/1.73 m2, with some of the overall renal clearance being achieved by renal tubular secretion.
The renal tubules also reabsorb memantine, possibly related to the involvement of cation transport proteins. Renal clearance decreases to 1/7 to 1/9 under alkaline urine conditions, and alkaline urine is seen with abrupt changes in diet (e.g., when switching from a meat to a vegetarian diet) or with ingestion of large amounts of alkaline gastric acid buffer.
Pharmacokinetic/pharmacodynamic relationship: At a dose of 20 mg daily, the concentration of memantine in the cerebrospinal fluid (CSF) reaches its ki value (ki=inhibition constant), which is 0.5 mmol in the human frontal cortex.
Pharmacology and Toxicology
Pharmacological effects
Studies have linked the sustained activation of central nervous system N-formyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate to Alzheimer’s disease. Memantine is a low to moderate affinity non-competitive NMDA receptor antagonist that binds preferentially to cation channels manipulated by NMDA receptors, which may be relevant to its therapeutic effects. No evidence was seen that memantine blocks or slows down neurodegenerative changes in patients with Alzheimer’s disease.
Memantine has low affinity for GABA, benzodiazepines, dopamine, adrenergic, histamine, glycine receptors, and voltage-dependent Ca2+, Na+, and K+ channels. In vitro studies have shown that memantine does not affect the reversible inhibitory effects of donepezil, galantamine or tacrine on acetylcholinesterase.
Toxicological studies
Genotoxicity
The results of Ames test, in vitro human lymphocyte chromosome aberration test, cytogenetic test for in vivo chromosome damage in rats, and in vivo micronucleus test in mice were all negative, and the results of V79 cell mutation test in Chinese hamsters were suspicious.
Reproductive toxicity
No effects on fertility or reproductive behavior were observed in female rats from 14 days before mating to the mating period, pregnancy and lactation, and in male rats from 60 days before mating to the mating period, when meperidine was given orally at doses up to 18 mg/kg/day (9 times the maximum recommended human dose [MRHD] based on mg/m2).
No malformations were observed in pregnant rats and rabbits given meperidine orally during the organogenesis period at the highest dose tested (18 and 30 mg/kg/day for rats and rabbits, respectively, equivalent to 9 and 30 times the MRHD at mg/m2 ).
Slight maternal toxicity, reduced pup weight, and increased incidence of unossified cervical vertebrae were observed in rats given meperidine orally at 18 mg/kg/day from pre-mating to late parturition. No such toxicity was observed at a dose of 6 mg/kg/day (3 times the MRHD at mg/m2).
Carcinogenicity
In a 113-week oral carcinogenicity test in mice, meperidine was administered at doses up to 40 mg/kg/day (10 times the MRHD at mg/m2) and no carcinogenicity was observed. In the oral carcinogenicity test in rats, doses of up to 40 mg/kg/day were administered for 71 weeks and then changed to 20 mg/kg/day for 128 weeks (20 and 10 times the MRHD, respectively, on a mg/m2 basis), and no carcinogenicity was observed.
Other
Memantine induced neuronal damage (vacuolization and necrosis) in multipolar cells and pyramidal cells in cortical layers III and IV of the posterior cingulate and posterior pressure neocortex in rats, similar to what is known to occur in rodents given other NMDA receptor antagonists. Lesions were found after a single administration of memantine. In a 14-day test in rats given memantine orally once daily, the unresponsive dose of neuronal necrosis was 6 times higher than that of MRHD (extrapolated from mg/m2).
In acute and repeated administration neurotoxicity tests in female rats, the transoral co-administration of memantine with donepezil resulted in an increased incidence, severity, and distribution of neurodegeneration compared to memantine alone, and the no-response dose for the co-administration was related to the human plasma exposure to memantine and donepezil.
The relevance of these findings to humans is unclear.
[Clinical Trials].
In a pivotal clinical study of monotherapy in a total of 252 patients with moderate to severe Alzheimer’s disease (baseline MMSE total score 3-14), the efficacy of the memantine treatment group was superior to that of the placebo group after 6 months of treatment (using the Clinician’s Interview-Based Impression of Change (CIBIC-Plus) scale). of Change (CIBIC-Plus): p=0.025; Alzheimer’s Disease Cooperative Study-Ability for Daily Living Questionnaire (ADCS-ADLsev): p=0.003; Severe Impairment Battery (SIB): p=0.002).
A total of 403 patients were enrolled in a pivotal clinical study of monotherapy for mild to moderate Alzheimer’s disease (baseline MMSE total score of 10-22). At the primary treatment endpoint (Alzheimer’s Disease Scale (ADAS-Cog) (p = 0.003) and CIBIC-plus (p = 0.004) at 24 weeks (Last Observation Carryover (LOCF)). Patient endpoints in the memantine group were superior to the placebo control group in a statistically significant manner. In another clinical study of monotherapy for mild to moderate Alzheimer’s disease (baseline MMSE total score 11-23), with a total of 470 randomized patients, the expected statistically significant significance was not obtained because the primary efficacy endpoint was not met at 24 weeks.
A meta-analysis of six placebo-controlled, 6-month (including monotherapy studies and studies in which patients took fixed doses of acetylcholinesterase inhibitors) phase III clinical studies conducted in patients with moderate to severe Alzheimer’s disease (MMSE total score <20) showed statistically significant improvements in cognition, overall level and different domains of functioning with memantine. When patients experienced deterioration in all three functional domains simultaneously, the number of patients in the placebo-treated group who experienced deterioration in all three functional domains was twice as high as in the memantine treated group (21% vs. 11%, p<0.0001), and the results of the study showed a statistically significant effect of memantine in preventing deterioration.
[Storage].
Seal and store at room temperature (10-30°C).
Store in a place out of reach of children.
Packaging
Aluminum-plastic blister package. 14 tablets/plate, 2 plates/box.
Expiration date
18 months
Execution Standard
Approval number】
【Drug marketing license holder
Name: Hefei Heyuan Pharmaceutical Co.
Registered address: No. 358, Ganquan Road, Hefei, Anhui Province
Postal Code: 230088
Contact：0551-65396612
Fax: 0551-65396612
Web address: http://www.heyuanpharm.com/
Manufacturer
Company name: Hefei Heyuan Pharmaceutical Co.
Address: No. 358, Ganquan Road, Hefei, Anhui Province
Postal Code: 230088
Contact：0551-65396612
Fax: 0551-65396612
Web address: http://www.heyuanpharm.com/