Memantine-NAN

Memantine

Film-coated tablets

Tablets, 10 mg: white round biconvex film-coated tablets scored on one side and debossed with “M9MN 10” on the other side. The tablet 10 mg can be divided into two equal parts.
Tablets, 20 mg: pink round biconvex film-coated tablets scored on one side and debossed with “M9MN 20” on the other side. The 20 mg tablet is not intended to be divided.

One tablet 10 mg contains:
Active substance: memantine hydrochloride – 10 mg;
Auxiliary substances: lactose monohydrate, microcrystalline cellulose, talc, anhydrous colloidal silicon dioxide, magnesium stearate;
Coating composition: Opadry II OY-L-28900 White: lactose monohydrate, hypromellose, titanium dioxide (E171), macrogol (polyethylene glycol) 4000.

One tablet 20 mg contains:
Active substance: memantine hydrochloride – 20 mg;
Auxiliary substances: lactose monohydrate, microcrystalline cellulose, talc, anhydrous colloidal silicon dioxide, magnesium stearate;
Coating composition: Opadry II 31F34070 Pink: lactose monohydrate, hypromellose, titanium dioxide (E171), macrogol (polyethylene glycol) 4000, iron oxide yellow (E172), iron oxide red (E172).

Psychoactivators. Other medications for treatment of dementia.

N06DX01

There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.

Treatment of adult patients with moderate to severe Alzheimer’s disease.

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s dementia. Therapy should only be started if a caregiver is available who will regularly monitor the intake of the medicinal product by the patient. Diagnosis should be made according to current guidelines. The tolerance and dosing of memantine should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of memantine and the patient’s tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as a therapeutic benefit is favourable and the patient tolerates treatment with memantine. Discontinuation of memantine should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Adults

The maximum daily dose is 20 mg. In order to reduce the risk of undesirable effects, the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows:

Week 1 (day 1-7):
The patient should take half a 10 mg tablet (5 mg) per day for 7 days.

Week 2 (day 8-14):
The patient should take one 10 mg tablet (10 mg) per day for 7 days.

Week 3 (day 15-21):
The patient should take one and a half 10 mg film-coated tablets (15 mg) per day for 7 days.

From Week 4 on:
The patient should take two 10 mg tablets (20 mg) or one 20 mg tablet per day.

The recommended maintenance dose is 20 mg per day.

Special populations

Elderly patients
On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (two 10 mg film-coated tablets or one 20 mg film-coated tablet once a day) as described above.

Patients with renal impairment
In patients with mildly impaired renal function (creatinine clearance 50 – 80 ml/min) no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance 30 – 49 ml/min) daily dose should be 10 mg per day. If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5–29 ml/min) daily dose should be 10 mg per day.

Patients with hepatic impairment
In patients with mild or moderate hepatic impaired function (Child-Pugh A and Child-Pugh B), no dose adjustment is needed. No data on the use of memantine in patients with severe hepatic impairment are available. Administration of memantine is not recommended in patients with severe hepatic impairment.

Paediatric population
Data on the efficacy and safety of memantine in children and adolescents under 18 years of age are not available.

Administration method
Tablets should be administered orally once a day and should be taken at the same time every day. The tablets can be taken with or without food.

Summary of the safety profile
In clinical trials the most frequently occurring adverse reactions with a higher incidence 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%).

List of adverse reactions
Adverse reactions are listed below, by system organ class and by frequency. Concurrent reactions are presented by classes of occurrence rate: very common (≥ 1/10), common (≥ 1/100, but < 1/10), uncommon (≥ 1/1000, but < 1/100), rare (≥ 1/10000, but < 1/1000), very rare (< 1/10000), frequency is unknown (cannot be estimated based on available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and invasions: uncommon – fungal infections.

Immune system disorders: common – hypersensitivity reactions.

Psychiatric disorders: common – somnolence; uncommon – confusion, hallucinations¹; not known – psychotic reactions².

Nervous system disorders: common – dizziness, balance disorders; uncommon – gait disturbances; very rare – seizures. Cardiac disorders: uncommon – cardiac failure.

Vascular disorders: common – hypertension; uncommon – venous thrombosis/thromboembolism.

Respiratory, thoracic and mediastinal disorders: common – dyspnoea.

Gastrointestinal disorders: common – constipation; uncommon – vomiting; not known – pancreatitis².

Hepatobiliary disorders: common – elevated liver function tests; not known – hepatitis.

General disorders and administration site conditions: common – headache, uncommon – fatigue.

¹ Hallucinations have mainly been observed in patients with severe Alzheimer’s disease.
² Isolated cases reported in post-marketing experience.

Alzheimer’s disease has been associated with depression, suicidal ideation and suicide. In post-marketing experience these reactions have been reported in patients treated with memantine.

Reporting of adverse reactions
If you have any adverse reactions, consult your doctor. This recommendation applies to any possible adverse reactions, including those not listed in this patient information leaflet. By reporting side effects, you help to gather more information on safety of Memantine-NAN.

Hypersensitivity to the active substance or to any of the excipients.

If taking a larger dose than prescribed by your doctor, immediately contact specialists to provide timely medical care!
Only limited experience with overdose is available from clinical studies and post-marketing experience.

Symptoms
Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been associated with either only symptoms of tiredness, weakness and/or diarrhoea or no symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, agitation, aggression, hallucination, and gait disturbance) and/or of gastrointestinal origin (vomiting and diarrhoea).

In the most extreme case of overdose, the patient survived the oral intake of a total of 2000 mg memantine. But overdose affected the central nervous system (coma for 10 days, and later diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The patient recovered without permanent sequelae.

In another case of a large overdose, the patient also survived and recovered. The patient had received 400 mg memantine orally. The patient experienced central nervous system symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, somnolence, stupor, and unconsciousness.

Treatment
In the event of overdose, treatment should be symptomatic. No specific antidote is available. Standard clinical procedures to remove active substance material, e.g., gastric lavage, carbo medicinalis (interruption of potential entero-hepatic recirculation), acidification of urine, forced diuresis should be used as appropriate.
In case of signs and symptoms of general central nervous system (CNS) overstimulation, careful symptomatic clinical treatment should be considered.

Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur:

• The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dose adjustment may be necessary.
• Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan. There is one published case report on a possible risk also for the combination of memantine and phenytoin.
• Other active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels.
• There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is co-administered with HCT or any combination with HCT.
• In post-marketing experience, isolated cases with international normalized ratio (INR) increases have been reported in patients concomitantly treated with warfarin. Although no causal relationship has been established, close monitoring of prothrombin time or INR is advisable for patients concomitantly treated with oral anticoagulants.

In single-dose pharmacokinetic (PK) studies in young healthy subjects, no relevant active substance-active substance interaction of memantine with glyburide/metformin or donepezil was observed.
In a clinical study in young healthy subjects, no relevant effect of memantine on the pharmacokinetics of galantamine was observed.
Memantine did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase, epoxide hydrolase or sulphation in vitro.

Inform your doctor about all medications you are taking. Consult your doctor before you start taking any medication during treatment with Memantine-NAN.

Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy.
Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse reactions (mainly central nervous system (CNS)-related) may be more frequent or more pronounced (see Section Interaction with other medicines).
Some factors that may raise urine pH may necessitate careful monitoring of the patient. These factors include drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or a massive ingestion of alkalising gastric buffers. Also, urine pH may be elevated by states of renal tubulary acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria.
In most clinical trials, patients with recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension were excluded. As a consequence, only limited data are available and patients with these conditions should be closely supervised.

Auxiliary substances
The medicinal product contains lactose, so do not use it in patients with such rare hereditary diseases as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

If you have one of the diseases or conditions listed above, be sure to consult your doctor before taking the medicinal product.

Pregnancy
There are no or limited amount of data from the use of memantine in pregnant women. Animal studies indicate a potential for reducing intrauterine growth at exposure levels, which are identical or slightly higher than at human exposure. The potential risk for humans is unknown. Memantine should not be used during pregnancy unless clearly necessary.

Breast-feeding
It is not known whether memantine is excreted in human breast milk but, taking into consideration the lipophilicity of the substance, this probably occurs. Women taking memantine should not breast-feed.

Moderate to severe Alzheimer’s disease usually causes impairment of driving performance and compromises the ability to use machinery. Furthermore, memantine has minor to moderate influence on the ability to drive and use machines such that outpatients should be warned to take special care.

15 tablets with 10 mg dosage or 10 tablets with 20 mg dosage in a blister made PVC film and flexible packing based on aluminum foil. 2 blisters (10 mg dosage) or 3 blisters (20 mg dosage) with a patient information leaflet, packed in a carton.

Memantine-NAN does not require any special storage conditions.
Keep away from children.

2 years. Do not use after the expiration date indicated on the packing.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en