Memantine Sandoz - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate - 131,000 mg, microcrystalline cellulose - 56,600 mg, silicon dioxide colloidal anhydrous - 0,800 mg, magnesium stearate - 1,600 mg;

sheath: Opapray II White 33G28707¹ (H464) 2.4 mg, lactose monohydrate 1.32 mg, macrogol 3000 0.48 mg, triacetin (glycerol triacetate) 0.36 mg, titanium dioxide (E171) 1.44 mg) 6,000 mg.

¹ - applied in the form of 15% aqueous suspension under conditions under which the carrier substance (water) evaporates.

Description:Oval, biconvex tablets, coated with film shell, white color with a risk on both sides.

Pharmacotherapeutic group:Dementia remedy

ATX: & nbsp

N.06.D.X.01 Memantine

N.06.D.X Other drugs for the treatment of dementia

Pharmacodynamics:

The adamantane derivative. Memantine - noncompetitive antagonist N-methyl-D-aspartate (NMDA) -receptors, has a modulating effect on glutamatergic transmission in the central nervous system (CNS) (reduces the excessive stimulating effect of cortical glutamate neurons on the neostriatum). Regulates ion transport, blocking calcium (Ca²⁺) channels, normalizes membrane potentials, facilitates the transfer of nerve impulses. Improves cognitive processes, increases daily activity.

Pharmacokinetics:

Suction: after intake quickly and completely absorbed from the gastrointestinal tract (GIT) (bioavailability ~ 100%). The intake of food does not affect the absorption of memantine, the time to reach the maximum concentration in the plasma (T_mOh) is from 3 to 8 hours. In patients with normal renal function cumulation memantine is not noted.

Distribution: the volume of distribution is about 10 l / kg. Connection with blood plasma proteins - 45%. When appointing a daily dose of 20 mg, the concentration of memantine in the blood plasma is 70-150 ng / ml (significant individual fluctuations).The concentration in the cerebrospinal fluid (CSF) is approximately 0.52 of the plasma one.

Metabolism: about 80% of the drug circulates in the blood in unchanged form, about 20% is metabolized (according to research - without the involvement of cytochrome P450). The main metabolites-N-3,5-dimethylgludantane (in the form of 2 isomers) and 1-nitroso-3,5-dimethyl-adamantane, do not have pharmacological activity.

Excretion: after oral administration ¹⁴C-memantine for about 20 days, about 84% of the drug is excreted from the body. More than 99% is excreted by the kidneys. In volunteers with normal renal function, the total clearance is 170 ml / min / 1.73 m², part of the total renal clearance is achieved through tubular secretion. Renal metabolism also includes tubular reabsorption, possibly mediated by cationic transport proteins. With alkalization of urine, the rate of removal of memantine can decrease by 7-9 times. The half-life (T_1/2) is 60-100 hours.

Linearity: studies conducted in volunteers showed a linear pharmacokinetics of memantine in the dose range of 10-40 mg.

Pharmacokinetic / pharmacodynamic dependence: when using memantine at a dose of 20 mg / day, the concentration in the cerebrospinal fluid corresponds to the value of the inhibition constant (ki),that for memantine is 0.5 μmol in the region of the frontal cortex of the brain.

Indications:Dementia of the Alzheimer's type of moderate and severe degree.

Contraindications:

- Hypersensitivity to memantine or to any of the auxiliary components;

- severe hepatic insufficiency (class C according to Child-Pugh classification);

- pregnancy and the period of breastfeeding;

- age under 18 years (due to lack of application data);

- deficiency of lactase, lactose intolerance, glucose-galactose malabsorption syndrome.

Carefully:

- Ischemic heart disease (angina pectoris, recent myocardial infarction);

- heart failure, III-IV functional class by classification NYHA;

- uncontrolled arterial hypertension;

- convulsive syndrome (including cramps in the anamnesis), epilepsy or risk factors for its development;

- thyrotoxicosis;

- simultaneous application with other antagonists NMDAreceptors (cf. section "Interaction with other drugs"");

- The presence of factors that increase pH urine, incl. severe urinary tract infections (cmsection "Special instructions");

- hepatic insufficiency (class A and B according to the Child-Pugh classification);

- renal failure (creatinine clearance (CK) <50 ml / min), see also See section "Dosing and Administration").

Pregnancy and lactation:

Application of the drug Memantine Sandoz® is contraindicated during pregnancy. Although there are no clinical data on the effects of the drug on the fetus, animal studies have indicated a possible slowdown in fetal development.

It is not known whether the memantine in breast milk, however, due to the lipophilicity of this drug, it is possible. Women taking the drug Memantine Sandoz® should stop breastfeeding. The effect of the drug on male or female fertility has not been noted.

Dosing and Administration:

Treatment with drug Memantine Sandoz® should be prescribed and controlled only by a doctor with expertise in the diagnosis and therapy of dementia. Therapy should be started only if the person, who regularly cares for the patient, will monitor the taking of the medication.

The tolerability and dose of the drug should be evaluated on a regular basis Memantine Sandoz® within three months after initiation of therapy.Supportive drug therapy Memantine Sandoz® should be continued as long as the clinical effect remains.

Inside. Memantine Sandoz® should be taken once a day at the same time, regardless of food intake.

Dose titration

Therapy should be started with a minimal dose, then increased until the recommended daily dose (20 mg / day).

The recommended initial dose is 5 mg / day, the dose should be consistently increased during the first 4 weeks until the recommended maintenance dose is achieved according to the following scheme:

- Week 1 (day 1-7): 5 mg / day;

- week 2 (day 8-14): 10 mg / day;

- week 3 (day 15-21): 15 mg / day;

- week 4 and further: 20 mg / day.

Special populations of patients

Elderly patients (over 65 years of age): correction of the dose is not required.

Age under 18 years of age: in connection with the lack of data on efficacy and safety, the use of memantine in children is contraindicated.

Renal insufficiency: with KK> 50 ml / min dose adjustment is not required. With QC 30-49 ml / min, after reaching a daily dose of 10 mg, the tolerability of the therapy should be assessed, with good tolerability for 7 days of treatment - a further dose increase is possible in accordance with the standard titration scheme.With QC 5-29 ml / min daily dose should not exceed 10 mg / day.

Liver failure: in patients with mild and moderate impairment of liver function (class A and B according to the Child-Pugh classification), dose adjustment is not required.

Side effects:

In clinical studies, the overall incidence of adverse events did not differ with memantine and placebo. As a rule, they were mild and moderate severity. The most common adverse events observed with a greater frequency in the memantine group compared with placebo were: dizziness (6.3% versus 5.6%, respectively), headache (5.2% vs. 3.9%), constipation ( 4.6% versus 2.6%), drowsiness (3.4% vs. 2.2%), and hypertension (4.1% vs. 2.8%).

According to the World Health Organization (WHO), the undesirable effects are classified according to the frequency of their development as follows: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Infectious and parasitic diseases	infrequently	fungal infections.
Violations from the sides of the blood and lymphatic systems	frequency unknown	agranulocytosis¹, leukopenia (including neutropenia)¹, pancytopenia¹, thrombocytopenia¹, thrombocytopenic purpura¹.
Violations from the immune side systems	often	hypersensitivity to the components of the drug;
Violations from the immune side systems	frequency unknown	Stevens-Johnson syndrome¹.
Disorders of the psyche	often	drowsiness;
	infrequently	confusion, hallucinations (mainly in patients with severe Alzheimer's disease), depression, sleep disorders, agitation;
	frequency unknown	suicidal thoughts¹, psychotic reactions¹.
Violations from side of the nervous systems	often	dizziness, imbalance;
	infrequently	violation of gait;
	rarely	seizures, epileptic seizures.
Violations from sides of the heart	infrequently	heart failure, heart defects.
Violations from sides of blood vessels	often	increased blood pressure;
Violations from sides of blood vessels	infrequently	venous thrombosis / thromboembolism.
Violations from hand respiratory systems, organs of the chest and mediastinum	often	dyspnea.
Disorders from the gastrointestinal tract	often	constipation;
	infrequently	nausea, vomiting;
	frequency unknown	pancreatitis¹.
Violations from side of the liver and bile excretory ways	often	increased activity of "liver" transaminases;
Violations from side of the liver and bile excretory ways	frequency unknown	hepatitis¹.
Violations from the kidneys and urinary tract ways	frequency unknown	acute renal failure¹.
Are common disorders and disorders in place introduction of	often	headache;
Are common disorders and disorders in place introduction of	infrequently	general weakness.

In Alzheimer's disease in patients in the post-registration period Depression, suicidal thoughts, and suicidal cases were recorded.

Overdose:

Symptoms

Dizziness, tremor, agitation, drowsiness, confusion, agitation, stupor, convulsions, psychosis, aggressiveness, hallucinations, gait unsteadiness, vomiting, diarrhea.

Treatment

There is no specific antidote. In case of an overdose, symptomatic therapy is performed, measures aimed at accelerated removal of the drug from the body (gastric lavage, activated charcoal intake, urine acidification, forced diuresis).

Clinical experience

Relatively large doses of the drug (200 mg and 105 mg / day for 3 days, respectively) caused symptoms of fatigue, weakness, diarrhea, some patients had no overdose symptoms.

After an overdose of the drug in a dose of 140 mg (the exact dose is unknown), the patient developed symptoms from the CNS, including confusion, drowsiness, dizziness, agitation, increased aggression, hallucinations and gait disturbance, and gastrointestinal symptoms (vomiting and diarrhea) .

After taking 400 mg memantine, there was a marked symptom from the CNS (anxiety, psychosis, visual hallucinations, convulsive alertness, drowsiness, stupor and loss of consciousness). The patient survived and recovered without any consequences.

After taking 2000 mg of memantine, the development of a coma (10 days) was observed, followed by the development of diplopia and agitation. The patient underwent symptomatic therapy, plasmapheresis. Symptoms of overdose resolved without the development of persistent complications.

Interaction:

With the simultaneous use of memantine and other antagonists NMDA-receptors (amantadine, ketamine, dextromethorphan) possibly an increase in the frequency and severity of unwanted reactions from the CNS. Possible development of pharmacotoxic psychosis.

Effects Levodopa, other dopaminergic agonists, anticholinergic drugs can be enhanced by the joint use of antagonists NMDA-receptors, including memantine. Possible decrease in effect barbiturates and neuroleptics.

With the simultaneous use of memantine and antispastic drugs (dantrolene, baclofen) can change their effect (increase or decrease), so that a dose adjustment may be required.

Such substances as cimetidine, ranitidine, procainamide, quinidine, quinine, nicotine use the same renal cationic transport system as amantadine, can also interact with memantine, leading to a potential risk of increasing the concentration of memantine in the blood plasma.

When combined use of memantine and hydrochlorothiazide the concentration of the latter in the plasma may decrease.

It is recommended that prothrombin time or an international normal ratio (INR) be carefully monitored when combined with warfarin, t. it is possible to increase INR.

Simultaneous appointment with antidepressants (selective serotonin reuptake inhibitors and monoamine oxidase inhibitors) requires careful monitoring of patients.

There is a report on the possible risk of developing psychosis with the combined use of a combination of memantine and phenytoin.

There was no clinically significant interaction with a single dose of memantine with glyburide / metformin or donepezil in healthy volunteers.

No effect of memantine on pharmacokinetics galantamine in healthy volunteers.

In studies in vitro memantine does not inhibit isoenzymes CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxyhydrolase and sulfation.

Special instructions:

If there are factors that may contribute to the pH urine (alkalization) may require careful monitoring of the patient's condition. These factors include: a radical change in the diet (for example, the transition from meat eating to a vegetarian diet), massive intake / administration of alkaline substances (sodium hydrogen carbonate solution), intake of carbonic anhydrase inhibitors, renal tubular acidosis, severe urinary tract infections, especially those caused by bacteria of the genus Proteus.

Patients who have recently had myocardial infarction and who have decompensated chronic heart failure (III-IV functional class by classification NYHA) or uncontrolled hypertension, were not included in most clinical trials of the drug. In this regard, the drug is recommended to be used with caution in these patients and under close supervision of the doctor.

It should avoid the appointment of memantine along with other antagonists NMDA-receptors (amantadine, ketamine, dextromethorphan), since it is possible to increase the frequency of development and severity of adverse reactions, mainly from the side of the central nervous system.

Special precautions when destroying an unused preparation

There is no need for special precautions when destroying an unused preparation.

Effect on the ability to drive transp. cf. and fur:

In patients with moderate and severe dementia, the ability to drive vehicles and manage complex mechanisms is usually impaired. Besides, memantine can cause a change in the reaction rate, so patients should refrain from driving vehicles or controlling mechanisms.

Form release / dosage:

Tablets, film-coated, 10 mg.

Packaging:

For 10 tablets in PVC / PVDC / Al blister. For 1, 2, 3 or 6 blisters in a pack of cardboard along with instructions for use.

For 14 tablets in PVC / PVDC / Al blister. By 2, 3, 4 or 7 blisters per pack of cardboard along with instructions for use.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003971

Date of registration:18.11.2016 / 28.09.2017

Expiration Date:18.11.2021

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SANDOZ ILAC SANAYI VE TICARET, A.S. Turkey

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp23.04.2018

Illustrated instructions

Instructions

Memantine Sandoz® (Memantin Sandoz®)