Limipranil

General characteristics. Structure:

Active agent, амисульприд 400 mg;
excipients: lactoses monohydrate, methyl cellulose 400 Wednesday, magnesium stearate, sodium carboxymethylstarch, cellulose microcrystallic;
film cover: methylmethacrylate, dimethylaminoethylmethacrylate and butylmethacrylate copolymer (Eudragit E 100); titanium dioxide (Е 171), talc, magnesium stearate, a macrogoal - 6000.

Description: oval biconvex tablets of white or almost white color, film coated, from risky.

Pharmacological properties:

Pharmacodynamics. Amisulprid selectively, with high affinity contacts the D2/D3 subtypes of dofaminergichesky receptors while has no affinity to the D1, D4 and D5 subtypes.
Unlike classical and atypical neuroleptics, амисульприд has no affinity to receptors of serotonin, H1 histamine, alpha and adrenergic and cholinergic receptors. Besides, амисульприд does not communicate with sigma sites.
When using in high doses blocks postsynaptic D2 the receptors which are localized in limbic structures (does not influence similar receptors in a striatum). Does not cause a katalepsy and does not lead to development of hypersensitivity of D2 - dopamine receptors after repeated treatment.
In low doses it preferential blocks presynaptic D2/D3 receptors, causing release of the dopamine responsible for its disingibitorny effects.
Such atypical pharmacological profile can serve as an explanation of antipsychotic effect of the amisulprid in high doses coming owing to blockade of postsynaptic dopamine receptors, and its efficiency concerning negative symptoms in low doses as a result of blockade of presynaptic dopamine receptors.
Besides, амисульприд to a lesser extent causes extrapyramidal side effects that can be connected with its preferential limbic activity.
At patients with schizophrenia with bad attacks амисульприд affects both secondary negative symptoms, and affective symptoms, such as depressive mood and a retardation.

Pharmacokinetics. At an amisulprid two absorbing peaks are noted: one is reached quickly, in an hour after introduction of a dose, and the second - between the 3 and 4 hour after reception. Concentration in plasma respectively makes 39 ± 3 and 54 ±4 ng/ml, after reception of 50 mg.
The volume of distribution is equal to 5,8 l/kg. As linkng with proteins of plasma is low (16%), interaction with other drugs is improbable.
Absolute bioavailability makes 48%. Amisulprid is metabolized poorly (about 4%), two inactive metabolites are identified. Cumulation of an amisulprid does not happen, and its pharmacokinetics remains invariable after reception of repeated doses. The elimination half-life (T1/2) of an amisulprid is equal to about 12 hours after reception of a peroral dose.
Amisulprid is brought with urine in not changed look. The renal clearance makes about 20 l/h or 330 ml/min.
The carbohydrate-rich food (containing 68% of liquid) authentically reduces AUC (the area under a curve concentration/time), it was not noted time of achievement of the maximum concentration and maximum concentration of an amisulprid, but changes of pharmacokinetics after reception of greasy food. However value of these observations in daily clinical practice is unknown.

Indications to use:

Treatment of the acute and chronic schizophrenia which is followed expressed productive (for example: nonsense, hallucinations, disorders of thinking) and/or negative (for example: affective flatness, lack of emotionality and leaving from communication) frustration, including patients with dominance of negative symptomatology.

Route of administration and doses:

At acute psychotic episodes use inside in a dose from 400 to 800 mg a day is recommended. In some cases the day dose can be increased to 1200 mg a day.
Doses should be raised taking into account individual portability.
Safety of the doses exceeding 1200 mg a day was not adequately studied therefore they should not be applied.
For patients with the mixed negative and productive symptoms of a dose it is necessary to select so that to provide optimum control over productive symptoms.
The supporting treatment has to be established individually at the level of minimal effective doses.
Selection of doses has to be individual.
In the doses exceeding 400 mg a day, Limipranil it is necessary to appoint in 2 receptions.
Patients of advanced age: Limipranil it is necessary to appoint with special precautions because of possible development of arterial hypotension or excessive sedation.

Renal failure:
Limipranil's removal is carried out through kidneys. At a renal failure the dose for patients with the clearance of creatinine (CC) of 30 - 60 ml/min. should be lowered on a half and to 1/3 for patients with KK from 10 to 30 ml/min.

Features of use:

As well as when using other neuroleptics, the malignant antipsychotic syndrome which is characterized by a hyperthermia, muscle tension, dysfunction of a peripheral nervous system, the increased kreatininfosfokinaza level can develop. At development of a hyperthermia, especially against the background of use of high doses, all antipsychotic drugs, including Limipranil, have to be cancelled.
Limipranil's removal is carried out by kidneys. In case of serious violations of function of kidneys it is necessary to lower a dose and to use the schemes of therapy described in the section "Dosage and Route of Administration".
As there is no experience of use of drug for patients with severe forms of renal frustration (KK <10 ml/min.), in their case is required extra care.
As drug is poorly metabolized, at abnormal liver functions of a dose decline it is not required.
Limipranil can reduce a convulsive threshold. Therefore patients with epilepsy in the anamnesis demand constant observation during therapy by Limipranil.
At advanced age Limipranil, as well as other neuroleptics, it is necessary to apply with special precautions because of possible risk of arterial hypotension or excessive sedation.
At Parkinson's disease, at purpose of antidofaminergichesky drugs and Limipranil, it is necessary to be careful because of a possible aggravation of symptoms.
Limipranil it is necessary to apply only if antipsychotic therapy cannot be avoided.
Prolongation of an interval of QT:
Limipranil causes dozozavisimy prolongation of an interval of QT. It is known that this effect increases risk of development of serious ventricular arrhythmias, and it amplifies in presence of bradycardia, a hypopotassemia, the inborn or acquired lengthening of an interval of QT.
Before purpose of drug and during treatment, depending on the clinical status of the patient, it is recommended to control factors which can promote development of this disturbance of a rhythm:

• bradycardia is lower than 55 blows/min.,
• hypopotassemia,
• inborn lengthening QT interval,
• simultaneous use of the drugs capable to cause the expressed bradycardia (<55 уд. / mines), a hypopotassemia, decrease in conductivity or lengthening of an interval of QT (see the section "Interactions with Other Medicines").
Influence on ability to drive the car and to perform the works requiring special attention
Amisulprid influences the speed of response therefore ability to manage vehicles or work with mechanisms can be weakened.

Side effects:

Frequent side effects (5 - 10%): sleeplessness, alarm, excitement.
Infrequent side effects (0,1 - 5%): drowsiness, gastrointestinal frustration, such as a lock, nausea, vomiting, dryness in a mouth.
As well as other neuroleptics амисульприд are caused by increase in level of prolactin in a blood plasma which is returned to former value after drug withdrawal. It can cause a galactorrhoea, an amenorrhea, a gynecomastia, stethalgias, impotence, and also increase in body weight.
Acute dystonia (spastic wryneck, okulogirny crises, lockjaw) can develop. This state is reversible and is adjusted by means of antiparkinsonichesky means. Frequency of emergence of extrapyramidal symptoms (a tremor, increase in arterial pressure, hypersalivation, an akathisia, a hypokinesia) which depend on a dose remains very low at treatment of patients with dominance of negative symptomatology with doses of 50 - 300 mg/days.
Messages on the late dyskinesia which is characterized by the rhythmical, involuntary movements preferential of language and/or persons belong usually to cases of prolonged use of drug. Antiparkinsonichesky means are inefficient, they can cause deterioration in symptoms.
Development of arterial hypotension and bradycardia, and also lengthening of an interval of QT is in rare instances possible, it is very rare - a ciliary arrhythmia.
It is occasionally reported about allergic reactions, increase in level of liver enzymes, generally transaminases and about cases of convulsive attacks.
There are very rare messages on cases of a malignant antipsychotic syndrome (see. "Special instructions").

Interaction with other medicines:

CONTRAINDICATED COMBINATIONS
Combinations which can cause ventricular arrhythmia like "pirouette":

• Antiarrhytmic drugs I of a class A, such as quinidine, Disopyramidum.
• Antiarrhytmic drugs III of a class, such as Amiodaronum, соталол.
• Other drugs, such as bepridit, цизаприд, сультоприд, thioridazine, intravenous erythromycin, intravenous Vincaminum, галофантрин, pentamidine, спарфлоксацин.
Levodopa: mutual antagonism of action of a levodopa and neuroleptics.
NOT RECOMMENDED COMBINATIONS
Amisulprid strengthens the oppressing action on alcohol TsNS.
THE COMBINATIONS DEMANDING EXTRA CARE
The medicines strengthening risk of developing of ventricular arrhythmia like "pirouette":
The drugs causing bradycardia such as beta adrenoblockers; the blockers of calcium channels causing bradycardia (diltiazem and verapamil); clonidine, гуанфацин, foxglove drugs.
Drugs which can cause a hypopotassemia: kaliyvyvodyashchy diuretics, laxatives, Amphotericinum In, glucocorticoids, tetrakozaktida (the hypopotassemia has to be corrected).
Neuroleptics, such as Pimozidum, haloperidol; antidepressants like Imipraminum; lithium.
COMBINATIONS WHICH SHOULD BE TAKEN INTO ACCOUNT
Combination to the drugs oppressing the TsNS function, including narcotic analgetics, antipsychotic drugs (neuroleptics), antihistaminic drugs with sedation, barbiturates, benzodiazepines and other anxiolytic drugs, the expressed strengthening of the oppressing action. With anti-hypertensive drugs - strengthening of anti-hypertensive action.

Contraindications:

• hypersensitivity to active ingredient or to other components of drug;
• the accompanying prolaktinzavisimy tumors, for example: prolaktinoma of a hypophysis and cancer of mammary glands;
• pheochromocytoma;
• children's age (up to 15 years);
• pregnancy, feeding by a breast;
• the women of childbearing age who are not using adequate contraception;
• combinations with the following medicines which can promote development of a ciliary arrhythmia: • antiarrhytmic Ia medicines of a class - quinidine, Disopyramidum, procaineamide;
• antiarrhytmic medicines III of a class - Amiodaronum, соталол;
• other medicines - bepridit, цизаприд, сультоприд, thioridazine, erythromycin (for in/in introductions), Vincaminum (for in/in introductions), галофантрин, pentamidine, спарфлоксацин;

• a combination with a levodopa;
(see the section "Interaction with Other Medicines").
With care - epilepsy, parkinsonism, advanced age, a renal failure.

Pregnancy and period of a lactation
Safety of an amisulprid during pregnancy is not established. Therefore, use of drug at pregnancy is not recommended unless the advantage justifies potential risk. It is unknown whether gets амисульприд into breast milk therefore breastfeeding during treatment is contraindicated.

Overdose:

The experience connected with overdose of an amisulprid is limited. It is reported about strengthening of the known pharmacological effects of drug. They include drowsiness and sedation, a coma, arterial hypotension and extrapyramidal symptoms.
In cases of acute overdose it is necessary to assume a possibility of interaction of several drugs.
There is no specific antidote for an amisulprid. The symptomatic treatment, is recommended strict observation of vital signs of an organism and continuous control of a condition of heart (risk of lengthening of an interval of QT) before recovery of a condition of the patient.
The hemodialysis is not effective.
In case of serious extrapyramidal symptoms, it is necessary to appoint anticholinergics.

Storage conditions:

At a temperature not above 30 °C. To store in the place, unavailable to children! Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 400 mg.
On 10 tablets in the blister from PVC / Aluminum foil. On 3, 6 or 10 blisters with the application instruction in a cardboard pack.
On 20, 40, 50 or 100 blisters together with application instructions in a cardboard box (for hospitals).