Instructions Tingrex film-coated tablets 10 mg blister No. 90
Composition
active ingredient: memantine;
1 tablet contains memantine hydrochloride 10 mg, which is equivalent to 8.31 mg of memantine;
excipients: lactose monohydrate; microcrystalline cellulose; talc; colloidal anhydrous silica; magnesium stearate;
shell: Opadry white 33G28707 (hypromellose (E 464); titanium dioxide (E 171); lactose monohydrate; macrogol 3000, triacetin), carnauba wax.
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, white or almost white, biconvex, oblong, with rounded ends, tapered from the inside, with a score on each side. The tablet can be divided into two halves.
Pharmacotherapeutic group
Psychoanaleptics. Other drugs for use in dementia. Memantine.
ATX code N06D X01.
Pharmacological properties
Pharmacodynamics.
Disturbances in glutamatergic neurotransmission, especially involving NMDA (N-methyl-D-aspartate) receptors, play an important role in the manifestation of symptoms and progression of neurodegenerative dementia.
Memantine is a voltage-gated, medium-affinity, noncompetitive NMDA receptor antagonist. Memantine modulates the effects of pathologically elevated glutamate levels, which can lead to neuronal dysfunction.
Clinical trials
The pivotal monotherapy study in patients with moderate to severe Alzheimer's disease (baseline MMSE score of 3–14) included a total of 252 outpatients. The beneficial effect of memantine treatment was evident after 6 months of treatment compared to placebo (observed-case analysis for clinician interview based on changes in CIBIC-plus (p = 0.025); ADCS-ADLsev (p = 0.003) and SIB (p = 0.002)).
The pivotal monotherapy study of memantine in mild to moderate Alzheimer's disease (baseline MMSE total score 10 to 22) enrolled 403 patients. Patients treated with memantine showed statistically significant improvement over placebo in the primary endpoints ADAS-cog (p = 0.003) and CIBIS-plus (p = 0.004) at 24 weeks (LOCF). In another monotherapy study in mild to moderate Alzheimer's disease, a total of 470 patients were randomized (baseline MMSE total score 11 to 23). In the prospectively defined primary analysis, statistical significance was not reached for the primary efficacy endpoint at 24 weeks.
A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total score < 20) from six phase III placebo-controlled 6-month studies (including monotherapy studies and studies in patients on a stable dose of acetylcholinesterase inhibitors) showed a statistically significant effect of memantine treatment on cognitive, general and functional domains.
When a patient experienced concomitant deterioration in all three domains, the results demonstrated a statistically significant effect of memantine in preventing deterioration; patients in the placebo group experienced deterioration in all three domains twice as often as patients taking memantine (21% vs. 11%, p < 0.0001).
Pharmacokinetics.
Absorption
The absolute bioavailability of memantine is approximately 100%, the time to reach maximum plasma concentration (Tmax) is from 3 to 8 hours. There is no evidence of an effect of food intake on absorption.
Distribution
A daily dose of 20 mg results in steady-state plasma concentrations of memantine ranging from 70 ng/ml to 150 ng/ml (0.5–1 μmol) with significant interindividual variation. With daily doses of 5 mg to 30 mg, the ratio of the drug in cerebrospinal fluid to serum is 0.52. Approximately 45% of memantine is bound to plasma proteins.
Biotransformation
In humans, approximately 80% of memantine circulates as the parent compound, the major metabolites do not have NMDA antagonistic properties. Cytochrome P450 involvement in metabolism has not been demonstrated in vitro.
In a study with oral administration of 14C-memantine, an average of 84% of the dose was eliminated within 20 days, with more than 99% of the dose excreted by the kidneys.
Breeding
Memantine is eliminated monoexponentially with a t1/2 of 60 to 100 hours. In volunteers with normal renal function, the total clearance (Cltot) is 170 ml/min/1.73 m2. The renal phase of memantine pharmacokinetics also includes tubular reabsorption.
The rate of renal elimination of memantine in alkaline urine may be reduced by 7–9 times. Alkalinization of urine may occur as a result of profound changes in diet, such as changing from a meat-rich diet to a vegetarian diet or as a result of intensive use of antacids.
Linearity
According to studies in volunteers, the pharmacokinetics of memantine are linear in the dose range of 10–40 mg.
Pharmacodynamic/pharmacokinetic relationship
At a dose of 20 mg memantine per day, the level of content in the cerebrospinal fluid corresponds to the ki value (inhibition constant) of memantine, which is 0.5 μmol in the frontal cortex of the human brain.
Indication
Alzheimer's disease from moderate to severe forms.
Contraindication
Hypersensitivity to the active substance or to any component of the drug.
Interaction with other medicinal products and other types of interactions
Concomitant use of memantine and amantadine should be avoided due to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA antagonists. The same may be true for ketamine and dextromethorphan. One published report also noted a possible risk of the combination of memantine and phenytoin.
The mechanism of action suggests that the effects of L-dopa, dopaminergic agonists and anticholinergics may be potentiated by concomitant use of NMDA antagonists such as memantine. The effects of barbiturates and neuroleptics may be attenuated. Concomitant use of memantine and antispasmodics, dantrolene or baclofen may modify their effects, which may require dose adjustment.
Other drugs such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine, which use the same renal cation transport system as amantadine, may also be able to interact with memantine, leading to a potential risk of increased plasma levels.
Concomitant use of memantine with hydrochlorothiazide (HCTZ) or any combination with HCTZ may result in a decrease in serum HCTZ levels.
There have been isolated reports of increased international normalized ratio (INR) with memantine in patients taking warfarin. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is necessary in patients taking concomitant oral anticoagulants.
In pharmacokinetic studies in healthy volunteers, no significant interaction effects of memantine with glyburide/metformin, donepezil, or galantamine were found.
Memantine is not an inhibitor of CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfation in vitro.
Application features
Caution should be exercised when prescribing the drug to patients with epilepsy, patients with a history of seizure episodes, as well as patients with risk factors for developing epilepsy.
The concomitant use of Tingrex® with N-methyl-D-aspartate (NMDA) antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine, and therefore adverse reactions (mainly related to the central nervous system (CNS)) may be more frequent or more severe.
Several factors that may increase urine pH may warrant close monitoring. These include major dietary changes, such as changing from a meat-rich diet to a vegetarian diet, or heavy use of antacids. In addition, urine pH may be elevated due to conditions such as renal tubular acidosis (RTA) or severe urinary tract infections caused by Proteus bacteria.
In most clinical trials, patients with recent myocardial infarction, decompensated congestive heart failure (New York Heart Association grades III–IV), and uncontrolled hypertension were excluded from the study. As a result, only limited data are available and patients with these conditions require close monitoring.
Tingrex® tablets contain lactose (as monohydrate). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
There are no data on the effects of memantine during pregnancy. Experimental studies in animals indicate the possibility of intrauterine growth retardation at exposure concentrations identical to or slightly higher than those used in humans. The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.
It is not known whether memantine is excreted in breast milk, but it is possible given the lipophilicity of the substance. Women taking memantine should refrain from breastfeeding.
Fertility
No negative effect of memantine on male or female fertility was observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Moderate to severe Alzheimer's disease usually impairs the ability to drive and use machines. Memantine also has a minor to moderate effect on the reaction time, so outpatients should be warned to exercise caution when driving or operating machinery.
Method of administration and doses
Treatment should be initiated and continued under the supervision of a physician. Therapy should only be initiated with a caregiver who will regularly monitor the patient's medication intake.
The tablets should be taken once a day at the same time each day. The tablets can be taken regardless of food intake.
Adults
The maximum daily dose is 20 mg. In order to reduce the risk of adverse reactions, the maintenance dose should be determined by gradually increasing the dosage by 5 mg per week during the first 3 weeks as follows:
Week 1 (days 1–7):
take ½ tablet (5 mg per day) for a week;
Week 2 (days 8–14):
take 1 tablet (10 mg per day) for a week;
Week 3 (days 15–21):
take 1½ tablets (15 mg per day) for a week;
starting from the 4th week:
take 2 tablets (20 mg per day) every day.
The recommended maintenance dose is 20 mg per day.
The duration of treatment should be determined individually by a physician experienced in the diagnosis and treatment of Alzheimer's disease. The tolerability and dosage of memantine should be assessed regularly, preferably within three months of starting treatment. The clinical effect of memantine and the patient's response to treatment should be assessed regularly thereafter in accordance with current clinical guidelines. Maintenance treatment may be continued as long as the therapeutic effect remains favourable and the patient's tolerance of memantine is good. Discontinuation of memantine should be considered if signs of therapeutic effect disappear or the patient's tolerance of treatment deteriorates.
Elderly patients
Based on the results of clinical studies, the recommended dose for patients aged 65 years and over is 20 mg per day (2 tablets of 10 mg once a day), as indicated above.
Kidney dysfunction
For patients with mild renal impairment (creatinine clearance 50–80 ml/min), no dose reduction is required. For patients with moderate renal impairment (creatinine clearance 30–49 ml/min), the daily dose should be reduced to 10 mg. The dose may be increased to 20 mg per day according to the standard regimen if there are no adverse reactions after at least 7 days of treatment. For patients with severe renal impairment (creatinine clearance 5–29 ml/min), the daily dose should be reduced to 10 mg.
Liver dysfunction
No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A and B). The use of memantine in patients with severe hepatic impairment is not recommended.
Children
The drug is not used in children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose
Experience is limited.
Symptoms
Relatively large overdoses (200 mg and 105 mg per day for 3 days, respectively) were either associated with symptoms of increased fatigue, weakness and/or diarrhea, or were asymptomatic. Overdoses up to 140 mg or an unknown dose have been associated with symptoms of CNS disorders (confusion, lethargy, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disorders (vomiting and diarrhea).
After taking 2000 mg of memantine, the patient developed coma for 10 days, later developing diplopia and agitation. After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.
In another case of a large overdose (400 mg memantine orally), the patient also survived and recovered. He experienced CNS disturbances such as anxiety, psychosis, visual hallucinations, convulsive readiness, drowsiness, stupor, and unconsciousness.
Treatment
Treatment is symptomatic, there is no specific antidote. Standard clinical procedures should be used to remove the active substance from the body, such as gastric lavage, administration of activated charcoal, methods of acidifying the urine reaction, forced diuresis.
In case of excessive general CNS stimulation, symptomatic treatment measures should be used with caution.
Side effects
General safety profile data
In clinical trials of memantine in patients with mild to severe dementia (1784 patients received memantine and 1595 patients received placebo), the overall incidence of adverse reactions was not different from that with placebo, and adverse events were usually mild to moderate in severity.
The most common adverse reactions, which occurred more frequently in the memantine group than in the placebo group, were dizziness (6.3% vs. 5.6%, respectively), headache (5.2% vs. 3.9%), constipation (4.6% vs. 2.6%), somnolence (3.4% vs. 2.2%), and hypertension (4.1% vs. 2.8%).
The adverse reactions observed during clinical trials and medical use are listed in the table below and are defined by frequency as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
| System, body, class | Frequency | Adverse reactions |
| Infections | infrequently | fungal diseases |
| On the part of the immune system | often | hypersensitivity |
| Mental disorders | drowsiness |
| infrequently | confusion of consciousness |
| infrequently | hallucinations1 |
| frequency unknown | psychotic reactions2 |
| From the nervous system | often | dizziness |
| often | disequilibrium |
| infrequently | gait disturbance |
| very rarely | convulsive seizures |
| From the heart | infrequently | heart failure |
| From the vascular side | often | arterial hypertension |
| infrequently | venous thrombosis/thromboembolism |
| Respiratory system | often | dyspnea |
Gastrointestinal tract | often | constipation |
| infrequently | vomiting |
| frequency unknown | pancreatitis2 |
| Liver and biliary tract disorders | often | increased liver function tests |
| frequency unknown | hepatitis |
| General violations | often | headache |
| infrequently | increased fatigue |
1 Hallucinations were mainly observed in patients with severe Alzheimer's disease.
2 Separate messages for medical use.
Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases have been reported with the medical use of memantine.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https://aisf.dec.gov.ua.
Expiration date
4 years.
Do not use after the expiry date stated on the packaging.
Storage conditions
Does not require special storage conditions.
Keep out of reach of children.
Packaging
10 tablets in a blister; 3 or 6 or 9 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
JSC "Grindex".
Location of the manufacturer and address of its place of business.
Krustpils Street, 53, Riga, LV-1057, Latvia.
Applicant
JSC "Grindex".
Location of the applicant.
Krustpils Street, 53, Riga, LV-1057, Latvia.
Phone/fax: +371 67083205 / +371 67083505
Email: grindeks@grindeks.lv
