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Amantadine sulfate - 100 mg

Pharmacological properties
pharmacodynamics. Amantadine has various pharmacological properties. It reveals the indirect property of striatal dopamine receptor agonist. Animal studies have shown that amantadine increases the extracellular concentration of dopamine both by increasing dopamine release and by blocking reuptake in presynaptic nerve cells. At therapeutic concentrations, amantadine inhibits the release of acetylcholine mediated by NMDA receptors, and thus may exert an anticholinergic effect. Amantadine has a synergistic effect with L-dopa.
Pharmacokinetics. After oral administration, amantadine is rapidly and completely absorbed from the gastrointestinal tract. The maximum concentration in the blood plasma (Cmax) is reached approximately 2–8 hours after taking a single dose of the drug. Easily soluble amantadine hydrochloride gives a higher concentration in the blood plasma than less soluble amantadine sulfate, which Cmax in plasma occurs later than that of the hydrochloride. Cmax of 0.5 μg/ml is achieved after a single oral dose of 250 mg of amantadine hydrochloride.
When taking the drug in a dose of 200 mg/day, the state of equilibrium concentration is reached after 4–7 days at a plasma concentration of 400–900 ng/ml. After taking 100 mg of amantadine sulfate, Cmax is 0.15 μg/ml. Plasma clearance is determined to be identical to renal clearance and is 17.7±10 l/h in healthy adult volunteers. The conditional volume of distribution is 4.2±1.9 l/kg and depends on the age of the patient; in adults - 6 l/kg.
T½ is 10–30 h (on average 15 h) and largely depends on the patient's age. In elderly male patients (62–72 years old), T½ is 30 hours. In patients with renal failure, the final T½ from blood plasma can be significantly prolonged (up to 68±10 h).
Amantadine binds to blood plasma proteins by approximately 67% (in vitro); about 33% is found in blood plasma in an unbound form. Penetrates through the blood-brain barrier, using saturable transport systems. It is excreted in urine almost unchanged (90% of a single dose), a small amount is excreted in feces.
The ability to dialyze amantadine is low, approximately 5% per dialysis.
Amantadine is not metabolized in the human body.

Indications Amantine
Parkinson's syndrome: treatment of symptoms of Parkinson's disease such as rigidity, tremor, hypokinesia and akinesia.
Extrapyramidal side effects of antipsychotics and other drugs: early dyskinesia, akathisia, and parkinsonism.

Application of Amantine
tablets should be taken by adults internally, with a small amount of liquid, after meals, preferably in the morning and/or afternoon. Due to the possible activating effect on the central nervous system (CNS), it is recommended to take the last dose of the drug no later than 4 p.m.
Single and daily dose.
By following the above precautions and taking into account contraindications, you can prevent a life-threatening adverse reaction - chaotic polymorphic ventricular tachycardia.
Treatment of patients with Parkinson's syndrome and movement disorders caused by the use of drugs should be carried out gradually, observing the dosage according to the therapeutic effect.
Treatment should be started by taking 1 tablet (100 mg of amantadine sulfate) of Amantin per day in the first 4-7 days, followed by an increase in the daily dose by 1 tablet once a week until reaching an effective therapeutic dose.
Usually, an effective dose is 1–3 tablets 2 times a day (200–600 mg of amantadine sulfate).
A daily dose of 100 mg (1 tablet) is recommended for elderly patients, in particular with states of agitation, confusion or delirium syndromes.If this dose is not effective, it can be carefully increased to 200 mg per day under the supervision of a doctor.
In the case of combined treatment with other antiparkinsonian drugs, the dose should be selected individually.
For patients previously treated with amantadine solution for injection, the starting dose should be higher.
With a sharp worsening of parkinsonian symptoms during an akinetic crisis, it is necessary to prescribe the introduction of a solution of amantadine sulfate.
Patients with renal failure.
Doses for patients with renal impairment should be adjusted according to glomerular filtration rate (GFR) as shown in the table:

GFR (ml/min) Dose of amantadine sulfate (mg) Interval between doses of amantadine sulfate
80–60 100 Every 12 hours
60 – 50 200 and 100* Every next day*
50 – 30,100 once a day
30 - 20,200 2 times a week
20 – 10,100 3 times a week
<10 and hemodialysis patients 200 and 100 1 time per week or 1 time every 2 weeks
*Achieved by alternately taking 1 tablet 1 time and 2 tablets 100 mg of amantadine sulfate 1 time.
The glomerular filtration rate (GFR) can be roughly calculated using the following equation:
Clcr = (140 ‒ age) × body weight/72 × creatinine
where,
Clcr — creatinine clearance in ml/min;
creatinine — serum creatinine in mg/10 

0 ml.
Creatinine clearance calculated according to this expression applies exclusively to men (the corresponding value for women is 85% of the given value) and can be equated with insulin clearance to determine GFR (120 ml/min for adults).
Amantadine is weakly dialyzed (approximately 5%).
The duration of treatment depends on the nature and severity of the course of the disease and is determined by the doctor. Patients should not interrupt treatment on their own.
Abrupt discontinuation of the drug should be avoided, as in this case, patients with Parkinson's disease may develop extrapyramidal symptoms, which sometimes include akinetic crisis, and the effect of discontinuation may sometimes manifest as delirium.
Children. The experience of using amantadine in children is insufficient, so the drug is not used in this age category.

Contraindication
- hypersensitivity to amantadine or to any component of the drug;
– epilepsy and other convulsive attacks;
- severe renal failure;
– gastrointestinal ulcer;
– decompensated heart failure (stage IV according to the classification developed by the New York Cardiology Association — NYNA);
– cardiomyopathy and myocarditis;
- atrioventricular block II and III degrees;
– bradycardia (less than 55 beats/min);
– prolonged QT interval (Bazett QTc > 420 ms) or with noticeable U-waves, or with congenital QT syndrome in the family history;
- severe ventricular arrhythmia, including chaotic polymorphic ventricular tachycardia;
- simultaneous treatment with budipin or other drugs that prolong the QT interval (see INTERACTIONS WITH OTHER DRUGS);
- low level of potassium or magnesium in the blood.

Side effect
adverse reactions to amantadine, which are more often mild and transient, usually appear within 2-4 days from the start of treatment and disappear quickly after stopping the drug.
The frequency of adverse reactions was assessed according to the following criteria:
very often (>1/10); often (>1/100 to <1/10); infrequent (>1/1000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); frequency unknown (cannot be estimated from available data).
On the part of the psyche: often — sleep disturbances and mental agitation.
Patients (especially the elderly) prone to mental disorders may experience paranoid exogenous psychoses accompanied by visual hallucinations when combined with anticholinergic drugs. Adverse reactions of this type may be observed more often if the drug Amantine is taken in combination with other antiparkinsonian drugs (such as levodopa, bromocriptine or memantine).
From the side of the blood and lymphatic system: very rarely - thrombocytopenia, leukopenia.
From the side of the nervous system: often - movement disorders; infrequently — dizziness, orthostatic disturbances; rarely - blurred vision; very rarely — epileptic seizures, usually after treatment with doses exceeding the recommended, symptoms of myoclonus and peripheral neuropathy, anxiety, headache, drowsiness, insomnia, weakness, fever, ataxia, slurred speech, impaired concentration, irritability, depression, paresthesia , confusion, disorientation, tremor, dyskinesia, stupor, suicidal thoughts and intentions, neuroleptic malignant syndrome, delirium, hypomania and mania, hallucinations, nightmares.
On the part of the organs of vision: rarely - blurred vision*; very rarely - temporary loss of vision*, increased sensitivity to light, corneal damage (point subepithelial opacity, which may be associated with superficial point keratitis), swelling of the corneal epithelium, decreased visual acuity, oculogyric crises, mydriasis; unknown - swelling of the cornea, disappears after stopping treatment.
Cardiac system: very rarely — cardiac arrhythmia (ventricular tachycardia, ventricular fibrillation, chaotic polymorphic ventricular tachycardia and prolongation of the QT interval), orthostatic hypotension, tachycardia, peripheral edema, heart failure. Most of these cases were due to overdose, concomitant use of certain drugs, or other risk factors (see CONTRAINDICATIONS and DRUG INTERACTIONS). Cardiac arrhythmia with tachycardia.
From the side of the vascular system: often — orthostatic dysregulation.
From the side of the digestive tract: often - nausea, feeling of dryness in the mouth; infrequently - anorexia, vomiting, constipation, diarrhea, reversible increase in the activity of liver enzymes.
From the side of the skin and subcutaneous tissue: often - "marble" skin (the appearance of a net-blue shade of the skin), sometimes associated with swelling of the ankle joint; very rarely — skin rashes, itching, increased sweating, increased photosensitivity, eczematous dermatitis.
From the side of the musculoskeletal and connective tissues: rhabdomyolysis may occur. Patients should be carefully monitored. If symptoms are observed, including myalgia, weakness, increased creatine kinase (creatine phosphokinase) or increased myoglobin in blood and urine, you should stop using this medicine 

which means and take appropriate measures. In addition, caution should be exercised due to the possibility of acute renal failure due to rhabdomyolysis.
From the genitourinary system: often — urinary retention in patients with prostatic hyperplasia, urinary incontinence, change in libido.
Others: hypersensitivity reactions with intolerance to any component of the drug.
*An ophthalmologist's examination is necessary as soon as symptoms of loss of visual acuity or blurred vision appear, in order to rule out possible corneal edema (see Special Precautions).

Features of application
special security measures.
Patients who simultaneously take antipsychotics and amantadine are at risk of developing neuroleptic malignant syndrome if amantadine is suddenly stopped.
Patients with kidney damage may experience intoxication.
It is necessary to be especially careful when prescribing the drug to patients with an organic brain syndrome or to patients prone to seizures, since seizures and exacerbation of already existing symptoms are possible (see sections "Method of administration and dosage" and "Side effects").
Patients with cardiovascular disorders require medical supervision during treatment with amantadine.
Patients with Parkinson's disease often have symptoms such as hypotension, increased salivation, increased sweating, elevated body temperature, heat build-up, edema, and depression. During the treatment of such patients, it is necessary to pay special attention to side reactions and interaction of amantadine with other medicinal products.
An ophthalmologist's examination is necessary if symptoms of loss of visual acuity or blurred vision appear, in order to rule out possible corneal edema. If corneal edema is diagnosed, amantadine should be discontinued. Corneal swelling caused by amantadine usually resolves within a month after stopping treatment.
Patients should inform their doctor if they have difficulty urinating.
Special care should be taken when using the drug in patients with:
– psychoses;
- liver function disorder;
- thyrotoxicosis;
– recurrent eczema;
- hypertrophy of the prostate gland;
- narrow-angle glaucoma;
– kidney failure (of varying severity); there is a risk of cumulation of amantadine due to impaired renal filtration (see also APPLICATION);
- agitation or confusion of consciousness;
- delirium syndrome or exogenous psychosis in the anamnesis;
– with simultaneous treatment with memantine (see INTERACTIONS WITH OTHER MEDICINES);
- with simultaneous use with drugs that affect the central nervous system (see INTERACTIONS WITH OTHER MEDICINES).
Before starting and after 1 and 3 weeks of treatment, an ECG (50 mm/s) and a manually determined Bazett QT interval (QTc) frequency correction should be performed. Such an ECG should be done before any subsequent dose increase and 2 weeks after it. In the future, an ECG must be performed at least once a year. Treatment should not be started or should be stopped if the initial QTc value exceeds 420 ms, if the QTc increases by more than 60 ms during treatment with the drug, or if the QTc value exceeds 480 ms, as well as in the presence of visible U-waves on the ECG.
Patients at risk of electrolyte imbalance due to, for example, treatment with diuretics, with frequent vomiting and/or diarrhea, patients taking insulin in crisis situations, or patients with renal or anorexic disorders should undergo examination and control of laboratory parameters and appropriate replenishment of electrolytes, especially potassium and magnesium.
If symptoms such as palpitations, dizziness, or fainting occur, amantadine should be stopped immediately and the patient should be observed for 24 hours for QT prolongation. If there is no prolongation of the QT interval, treatment with the drug can be resumed, taking into account contraindications and interactions.
In patients with pacemakers, the exact determination of the QT time is impossible, so the decision to use amantadine should be made individually after consultation with a cardiologist.
Adjunctive use of amantadine for the prevention and treatment of influenza caused by virus A is not recommended due to the risk of overdose.
Treatment with amantadine should not be stopped suddenly, as this can lead to worsening of Parkinson's disease, the appearance of symptoms characteristic of neuroleptic malignant syndrome, as well as the development of cognitive disorders, such as: catatonia, confusion, disorientation, deterioration of mental status, delirium.
Amantadine should not be abruptly discontinued in patients receiving concomitant antipsychotics due to the potential risk of neuroleptic-induced catatonia.
Suicide attempts and suicidal thoughts have been reported in patients receiving amantadine. In order to prevent the emergence of suicidal thoughts and intentions, the drug should be prescribed in minimum effective doses.
In some patients with long-term use of the drug

peripheral edema may occur. This should be taken into account by persons with chronic heart failure.
The drug should not be used in patients with closed-angle glaucoma.
The drug contains lactose, so patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use amantadine.
Use during pregnancy or breastfeeding. Amantadine is contraindicated for pregnant women and women planning pregnancy. The drug is contraindicated during breastfeeding, as it penetrates into breast milk. If it is necessary to use the drug, breastfeeding should be stopped.
The ability to influence the speed of reaction when driving vehicles or other mechanisms. Amantadine can reduce the concentration of attention and reaction speed, cause dizziness, decrease in visual acuity, so patients should be warned about the potential danger when driving a car or working with other mechanisms.

Interaction with other medicinal products
before starting to take other drugs in combination with amantadine, it is necessary to carefully read the instructions for medical use regarding the possible interaction of these drugs with amantadine, which can lead to prolongation of the QT interval. A combination of amantadine with other antiparkinsonian drugs is possible. To avoid side effects (such as psychotic reactions), the dose of other drugs or their combinations should be reduced.
It is known that special interaction studies after simultaneous administration of amantadine and other antiparkinsonian agents (such as levodopa, bromocriptine, memantine, trihexylphenidyl, etc.) have not been conducted (pay attention to side effects).
The simultaneous use of amantadine and any other types of drugs or active ingredients listed below can lead to the following types of interactions.
Anticholinergic drugs. Enhancement of adverse reactions (confusion and hallucinations), anticholinergic agents (such as trihexylphenidyl, benzatropine, scopolamine, biperiden, orphenadrine, etc.).
Sympathomimetics with a direct effect on the central nervous system. Enhancement of the main effect of amantadine.
Alcohol. Decreased alcohol tolerance.
Levodopa (antiparkinsonian drug). Mutual strengthening of the therapeutic action. Therefore, levodopa can be prescribed simultaneously with amantadine.
Other antiparkinsonian drugs. Memantine can increase the action and side effects of amantadine (it is important to pay attention to the section SPECIAL USE), therefore, simultaneous use with memantine should be avoided.
Other medicines. The simultaneous use of diuretics such as triamterene/hydrochlorothiazide can reduce the removal of amantadine from the blood plasma, which leads to the formation of a toxic concentration of the latter in the blood plasma. Therefore, the simultaneous use of this combination should be avoided.
The simultaneous use of amantadine and drugs that prolong the QT interval is contraindicated. They include:
- certain class IA antiarrhythmics (eg quinidine, disopyramide, procainamide) and class III (eg amiodarone, sotalol);
- certain neuroleptics (for example, thioridazine, chlorpromazine, haloperidol, pimozide);
- certain tricyclic and tetracyclic antidepressants (for example, amitriptyline);
- certain antihistamines (for example, astemizole, terfenadine);
- certain macrolide antibiotics (for example, erythromycin, clarithromycin);
- certain gyrase inhibitors (for example, sparfloxacin);
– azole antifungals and other drugs such as budipin, halofantrine, cotrimoxazole, pentamidine, cisapride and bepridil.

Overdose
it is always necessary to take into account the possibility of multiple intoxication, for example, taking more than one drug for the purpose of suicide.
Symptoms Symptoms of acute toxic psychosis in the form of confusion with visual hallucinations, which sometimes include coma and myoclonus and can be observed after simultaneous administration of amantadine and other antiparkinsonian drugs, occupy a significant place in amantadine overdose. Excessive excitement, tremor, ataxia, blurred vision, lethargy, depression, dysarthria, neuromuscular disorders, hyperreflexia, motor restlessness, convulsions, extrapyramidal phenomena, torsion spasms, dilated pupils, dysphagia, confusion, disorientation, delirium, myoclonus, nausea, vomiting, dry mouth, hyperventilation, pulmonary edema, respiratory failure, respiratory distress syndrome, hypertension, cardiac arrhythmia, tachycardia, angina attack, cardiac arrest.
Possible impairment of kidney function, including increased urea nitrogen and decreased creatinine clearance, urinary retention.
Treatment. No specific medical treatment or antidote is known. To prevent absorption of the drug, it is necessary to induce vomiting and/or wash the stomach (if the patient is unconscious), use activated charcoal. In case of life-threatening intoxication, resuscitation measures are necessary. It is necessary to take therapeutic measures, to ensure adequate support of the vital functions of the body 

hydration, possibly sedation, anticonvulsant and antiarrhythmic measures. For the treatment of the neurotoxic symptoms described above, intravenous physostigmine can be used at a dose of 1–2 mg every 2 h for adults and from 2 × 0.5 mg with an interval of 5–10 min to a maximum dose of 2 mg for children.
Close monitoring of patients at risk of QT prolongation and chaotic polymorphic ventricular tachycardia, such as electrolyte imbalance (including hypokalemia and hypomagnesemia) or bradycardia, is recommended. Due to the low ability of amantadine to dialyze (almost 5%), hemodialysis is not recommended.

Storage conditions
in a place inaccessible to children, in the original packaging at a temperature not higher than 25 °C.