Rozumin

ROSUMIN
ROSUMIN

Composition:

Film-coated tablets, 10 mg:

Active substance: memantine hydrochloride;

1 film-coated tablet contains memantine hydrochloride 10 mg (mg);

Excipients: silicified microcrystalline cellulose, sodium croscarmellose,

talc, magnesium stearate, Instacoat Universal White A05G10005.

Film-coated tablets, 20 mg:

Active substance: memantine hydrochloride;

1 film-coated tablet contains memantine hydrochloride 20 mg (mg);

Excipients: silicified microcrystalline cellulose, sodium croscarmellose,

talc, magnesium stearate, Instacoat Universal Brown ICG-U-10338.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: capsule-shaped, film-coated tablets, white or almost white, with "CL 29" engraved on one side and a score line on both sides;

20 mg tablets: capsule-shaped, film-coated tablets, brown, with "CL 30" engraved on one side.

Pharmacotherapeutic group.

Psychoanaleptics. Other agents used in dementia. Memantine.

ATC code N06D X01.

Pharmacological properties.

Pharmacodynamics.

Memantine is a voltage-dependent, moderate-affinity, non-competitive antagonist of NMDA receptors. It modulates the effects of pathologically elevated tonic levels of glutamate, which may lead to neuronal dysfunction. Impaired glutamatergic neurotransmission, particularly involving NMDA (N-methyl-D-aspartate) receptors, plays a significant role in the symptoms and progression of neurodegenerative dementia.

Pharmacokinetics.

Absorption. Memantine has an absolute bioavailability of approximately 100%; the time to reach peak plasma concentration (Tmax) ranges from 3 to 8 hours. No food effect on memantine absorption has been observed.

Distribution. Daily doses of 20 mg result in a steady-state plasma concentration of memantine ranging from 70 to 150 ng/mL (0.5–1 µmol), with considerable inter-individual variability. With daily doses of 5 to 30 mg, the ratio of drug concentration in cerebrospinal fluid to plasma is 0.52. Approximately 45% of memantine is bound to plasma proteins.

Biotransformation. In humans, about 80% of memantine circulates as the parent compound. The main metabolites are: N-3,5-dimethyl-gludantan, isomeric mixture of 4- and 6-hydroxymemantine, and 1-nitroso-3,5-dimethyl-adamantane. The primary metabolites lack NMDA-antagonistic properties. No involvement of cytochrome P450 in metabolism has been observed in vitro.

Elimination. Memantine is eliminated monoexponentially with a terminal t½ of 60 to 100 hours. In volunteers with normal renal function, total clearance (Cltot) is 170 mL/min/1.73 m². Renal pharmacokinetics of memantine also includes tubular reabsorption.

The rate of renal elimination of memantine may decrease 7–9 times under alkaline urine conditions. Alkalinization of urine may occur due to significant dietary changes, e.g., switching from a meat-rich diet to a vegetarian one, or due to intensive intake of antacid agents.

Linearity. Pharmacokinetics are linear within the dose range of 10–40 mg.

Pharmacodynamic/pharmacokinetic relationship

At a dose of 20 mg memantine per day, the concentration in cerebrospinal fluid corresponds to the ki (inhibition constant) of memantine, which is 0.5 µmol in the frontal cortex region of the human brain.

Clinical characteristics.

Indications.

Alzheimer's disease from mild to severe stages.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

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 applies to ketamine and dextromethorphan. One published report also mentioned a possible risk with the combination of memantine and phenytoin.

The mechanism of action suggests possible enhancement of the effects of L-dopa, dopaminergic agonists, and anticholinergic agents when used concomitantly with NMDA antagonists such as memantine. Effects of barbiturates and neuroleptic agents may be diminished. Concomitant use of memantine with muscle relaxants, dantrolene or baclofen may modify their effects and necessitate dose adjustments.

Other medicinal products such as cimetidine, ranitidine, procainamide, quinidine, quinine, and nicotine, which use the same renal cationic transport system as amantadine, may also potentially interact with memantine, increasing the risk of elevated plasma levels.

Concomitant administration of memantine with hydrochlorothiazide (HCTZ) or any HCTZ-containing combination may reduce serum levels of HCTZ.

There have been reports of isolated cases of increased international normalized ratio (INR) in patients taking warfarin while on memantine. Although a causal relationship has not been established, careful monitoring of prothrombin time or INR is required in patients receiving oral anticoagulants concomitantly.

In pharmacokinetic studies involving healthy volunteers, no significant interaction effects between memantine and glipizide/metformin, donepezil, or galantamine were observed.

Memantine in vitro is not an inhibitor of cytochrome P450 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin-containing monooxygenase, epoxide hydrolase, or sulfotransferase.

Special precautions.

The medicinal product should be prescribed with caution in patients with epilepsy, patients with a history of seizures, or patients with risk factors for developing epilepsy.

Concomitant use 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 may therefore cause adverse reactions (mainly of the central nervous system), which may occur more frequently or more severely.

Some factors that may increase urine pH require careful patient monitoring. These include significant dietary changes, such as switching from a meat-rich diet to a vegetarian one, or intensive intake of alkalinizing antacids. Additionally, urine pH may increase in conditions such as renal tubular acidosis (RTA) and severe urinary tract infections caused by Proteus bacteria.

Patients who recently had myocardial infarction, decompensated congestive heart failure (NYHA class III–IV), or uncontrolled hypertension were excluded from most clinical trials. Therefore, data are limited, and such patients require careful monitoring.

Use during pregnancy or breastfeeding.

There are no clinical data on the effects of memantine during pregnancy. Animal studies indicate possible intrauterine growth retardation at concentrations equal to or slightly higher than those used in humans. The potential risk to humans is unknown. Memantine should not be used during pregnancy except in cases where clearly necessary.

It is unknown whether memantine is excreted in breast milk, although this is possible given the lipophilicity of the substance. Women taking memantine should avoid breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Alzheimer's disease from moderate to severe stages usually impairs the ability to drive and operate machinery. Additionally, memantine has a minor or moderate effect on human reaction speed; therefore, outpatient patients should be warned to exercise particular caution when driving or operating equipment.

Method of administration and dosage.

Treatment should be initiated and supervised by a physician. Therapy should only be started if a caregiver is available to regularly monitor the patient's intake of the medicinal product.

Tablets should be taken once daily at the same time each day. Tablets may be taken independently of food intake.

Adults.

The maximum daily dose is 20 mg. To reduce the risk of adverse reactions, the maintenance dose is achieved by gradually increasing the dose by 5 mg per week over the first 3 weeks as follows:

Week 1 (days 1–7): take 5 mg daily;

Week 2 (days 8–14): take 10 mg daily;

Week 3 (days 15–21): take 15 mg daily;

from week 4 onwards: take 2 tablets (20 mg daily).

The recommended maintenance dose is 20 mg daily.

Treatment duration is individually determined by a physician experienced in diagnosing and treating Alzheimer's disease. Tolerance and dosing of memantine should be regularly assessed, especially during the first 3 months of treatment. Thereafter, the clinical effect of memantine and the patient's response to treatment should be regularly evaluated according to current clinical guidelines. Maintenance therapy may continue as long as the therapeutic effect remains favorable and tolerance is good.

Discontinuation of memantine therapy should be considered if therapeutic effects disappear or tolerance worsens.

Elderly patients.

Based on clinical trial results, the recommended dose for patients aged 65 years and older is 20 mg daily (2 tablets of 10 mg once daily), as stated above. Renal impairment.

No dose reduction is required for patients with mild renal impairment (creatinine clearance 50–80 mL/min). 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 daily following the standard titration scheme if no adverse reactions occur 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.

Hepatic impairment.

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A, B). Use of memantine is not recommended in patients with severe hepatic impairment.

Children.

The medicinal product is not used in children due to insufficient data on safety and efficacy.

Overdose.

Experience is limited.

Symptoms

Administration of relatively high doses (200 mg and 105 mg daily for 3 days) was associated with symptoms such as fatigue, weakness, and/or diarrhea. Absence of symptoms is possible. In cases of overdose with doses below 140 mg or when the dose was unknown, patients experienced central nervous system (CNS) disturbances (confusion, hypersomnia, somnolence, dizziness, agitation, aggression, hallucinations, gait disturbances) and/or gastrointestinal disturbances (vomiting, diarrhea).

After overdose with a high dose of memantine (2000 mg), a patient experienced CNS disturbances (the patient was comatose for 10 days, followed by diplopia and agitation). After symptomatic treatment and plasmapheresis, the patient recovered without sequelae.

In another case of high-dose overdose, the patient also survived and recovered. CNS symptoms observed included restlessness, psychosis, visual hallucinations, increased seizure susceptibility, somnolence, stupor, and loss of consciousness.

Treatment

In case of overdose, treatment should be symptomatic. There is no specific antidote. Standard clinical procedures aimed at removing the drug from the patient's body include gastric lavage and administration of activated charcoal (to interrupt possible enterohepatic recirculation). If necessary, procedures such as acidification of urine and forced diuresis should be applied.

If symptoms of excessive CNS stimulation are present, symptomatic clinical treatment should be initiated.

Adverse reactions.

During clinical trials of memantine, the overall frequency of adverse events did not differ from that observed with placebo, and adverse events were usually mild or moderate in severity.

The adverse reactions listed below were observed during clinical trials and medical use. Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); unknown (cannot be estimated from available data).

1 Hallucinations were mainly observed in patients with severe Alzheimer's disease.

2 Isolated cases were reported in the post-marketing period.

Alzheimer's disease is associated with depression, suicidal ideation, and suicide. Such cases were also reported during the post-marketing use of memantine.

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging. Keep out of reach of children.

Packaging.

14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.