Mentino 5 mg Orodispersible tablets

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.

Posology

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 Mentino should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of Mentino 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 Mentino. Discontinuation of Mentino should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.

Adults

Dose titration

The recommended starting dose is 5 mg per day which is stepwise increased over the first 4 weeks of treatment reaching the recommended maintenance dose as follows:

Week 1 (day 1-7)

The patient should take one 5 mg tablet per day (light pink round, flat, speckled tablets with beveled edges, a diameter of 7 mm and engraved with “5” on one side) for 7 days.

Week 2 (day 8-14)

The patient should take one 10 mg tablet per day (light pink, round, flat, speckled tablets with beveled edges, a diameter of 9 mm and engraved with “10” on one side) for 7 days.

Week 3 (day 15-21)

The patient should take one 15 mg tablet per day (light pink, round, flat, speckled tablets with beveled edges, a diameter of 11 mm and engraved with “15” on one side) for 7 days.

Week 4 (day 22-28)

The patient should take one 20 mg tablet per day (light pink, round, flat, speckled tablets with beveled edges, a diameter of 12 mm and engraved with “20” on one side) for 7 days.

The maximum daily dose is 20 mg per day.

Maintenance dose

The recommended maintenance dose is 20 mg per day.

Elderly

On the basis of the clinical studies, the recommended dose for patients over the age of 65 years is 20 mg per day (20 mg once a day) as described above.

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.

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 Mentino in patients with severe hepatic impairment are available. Administration of Mentino is not recommended in patients with severe hepatic impairment.

Paediatric population

No data are available.

Method of administration

Mentino 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.

The tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water, according to patient preference.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 also section 4.5).

Some factors that may raise urine pH (see section 5.2 “Elimination”) 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.

Mentino contains Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Mentino contains Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Mentino contains Aspartame

Aspartame is hydrolysed in the gastrointestinal tract when orally ingested. One of the major hydrolysis products is phenylalanine.

Due to the pharmacological effects and the mechanism of action of Mentino 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 Mentino with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dose adjustment may be necessary.

• Concomitant use of Mentino 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 (see also section 4.4). There is one published case report on a possible risk also for the combination of Mentino 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 Mentino leading to a potential risk of increased plasma levels.

• There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when Mentino 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 Mentino with glyburide/metformin or donepezil was observed.

In a clinical study in young healthy subjects, no relevant effect of Mentino on the pharmacokinetics of galantamine was observed.

Mentino did not inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin containing monooxygenase, epoxide hydrolase or sulphation in vitro.

Pregnancy

There are no or limited amount of data from the use of Mentino 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 (see section 5.3). The potential risk for humans is unknown. Mentino should not be used during pregnancy unless clearly necessary.

Breast-feeding

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

Fertility

No adverse reactions of Mentino were noted on male and female fertility.

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

Summary of the safety profile

In clinical trials in mild to severe dementia, involving 1,784 patients treated with Mentino and 1,595 patients treated with placebo, the overall incidence rate of adverse reactions with Mentino did not differ from those with placebo; the adverse reactions were usually mild to moderate in severity. The most frequently occurring adverse reactions with a higher incidence in the Mentino 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%).

Tabulated list of adverse reactions

The following Adverse Reactions listed in the Table below have been accumulated in clinical studies with Mentino and since its introduction in the market.

Adverse reactions are ranked according to system organ class, using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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 suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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 Mentino with effects on 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 Mentino 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 for intoxication or overdose 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.

Pharmacotherapeutic group: Psychoanaleptics. Other Anti-dementia drugs, ATC code: 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.

Mentino 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.

Clinical studies

A pivotal monotherapy study in a population of patients suffering from moderate to severe Alzheimer's disease (mini mental state examination (MMSE) total scores at baseline of 3 - 14) included a total of 252 outpatients. The study showed beneficial effects of Mentino treatment in comparison to placebo at 6 months (observed cases analysis for the clinician's interview based impression of change (CIBIC-plus): p=0.025; Alzheimer's disease cooperative study – activities of daily living (ADCS-ADLsev): p=0.003; severe impairment battery (SIB): p=0.002).

A pivotal monotherapy study of Mentino in the treatment of mild to moderate Alzheimer's disease (MMSE total scores at baseline of 10 to 22) included 403 patients. Memantine-treated patients showed a statistically significantly better effect than placebo-treated patients on the primary endpoints: Alzheimer's disease assessment scale (ADAS-cog) (p=0.003) and CIBIC-plus (p=0.004) at week 24 last observation carried forward (LOCF). In another monotherapy study in mild to moderate Alzheimer's disease a total of 470 patients (MMSE total scores at baseline of 11-23) were randomised. In the prospectively defined primary analysis statistical significance was not reached at the primary efficacy endpoint at week 24.

A meta-analysis of patients with moderate to severe Alzheimer's disease (MMSE total scores < 20) from the six phase III, placebo-controlled, 6-month studies (including monotherapy studies and studies with patients on a stable dose of acetylcholinesterase inhibitors) showed that there was a statistically significant effect in favour of Mentino treatment for the cognitive, global, and functional domains. When patients were identified with concurrent worsening in all three domains, results showed a statistically significant effect of Mentino in preventing worsening, as twice as many placebo-treated patients as memantine-treated patients showed worsening in all three domains (21% vs. 11%, p<0.0001).

Absorption

Mentino has an absolute bioavailability of approximately 100%. T_max is between 3 and 8 hours. There is no indication that food influences the absorption of memantine.

Distribution

Daily doses of 20 mg lead to steady-state plasma concentrations of Mentino ranging from 70 to 150 ng/ml (0.5 - 1 μmol) with large interindividual variations. When daily doses of 5 to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was calculated. The volume of distribution is around 10 l/kg. About 45% of Mentino is bound to plasma-proteins.

Biotransformation

In man, about 80% of the circulating memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5- dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P 450 catalysed metabolism has been detected in vitro.

In a study using orally administered ¹⁴C-memantine, a mean of 84% of the dose was recovered within 20 days, more than 99% being excreted renally.

Elimination

Mentino is eliminated in a monoexponential manner with a terminal t½ of 60 to 100 hours. In volunteers with normal kidney function, total clearance (Cl_tot) amounts to 170 ml/min/1.73 m² and part of total renal clearance is achieved by tubular secretion.

Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of Mentino under alkaline urine conditions may be reduced by a factor of 7 to 9 (see section 4.4). Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a vegetarian diet, or from the massive ingestion of alkalizing gastric buffers.

Linearity

Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10 to 40 mg.

Pharmacokinetic/pharmacodynamic relationship

At a dose of Mentino of 20 mg per day the CSF levels match the k_i-value (k_i = inhibition constant) of memantine, which is 0.5 μmol in human frontal cortex.

In short term studies in rats, Mentino like other NMDA-antagonists have induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long term studies in rodents nor in non-rodents, the clinical relevance of these findings is unknown.

Ocular changes were inconsistently observed in repeat dose toxicity studies in rodents and dogs, but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with Mentino did not disclose any ocular changes.

Phospholipidosis in pulmonary macrophages due to accumulation of Mentino in lysosomes was observed in rodents. This effect is known from other active substances with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolization observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.

No genotoxicity has been observed following testing of Mentino in standard assays. There was no evidence of any carcinogenicity in life long studies in mice and rats. Mentino was not teratogenic in rats and rabbits, even at maternally toxic doses, and no adverse effects of Mentino were noted on fertility. In rats, foetal growth reduction was noted at exposure levels, which are identical or slightly higher than at human exposure.

Polacrilin

Sodium hydroxide (E 524)

Water, purified

Lactose monohydrate

Cellulose, microcrystalline (E 460)

Mannitol (E 421)

Croscarmellose sodium (E 468)

Aspartame (E 951)

Silica, colloidal anhydrous

Iron oxide red (E 172)

Flavor peppermint

Magnesium stearate (E 572)

Not applicable

36 months

This medicinal product does not require any special storage conditions.

Aluminium/ peelable Aluminium blisters

Each pack contains 7 orodispersible tablets.

No Special requirements.