What does dispersible mean? Pharmaceutical product, dispersible tablet, method of its production. Trade name of the drug

Flemoxin is a generic version of one of the most popular antibiotics in the world -. The original drug was developed by British pharmacists in the 60s of the last century. Amoxicillin appeared on the pharmaceutical market in the early 70s.

Amoxicillin is, without a doubt, one of the safest broad-spectrum antibacterial drugs. According to some reports, this penicillin antibiotic is almost the most prescribed medicine in pediatrics. Almost every reputable pharmaceutical company considers it its duty to release its own Amoxicillin. The Japanese corporation Astellas Pharma also succeeded in this matter by developing Flemoxin.

Flemoxin Solutab stands out from the monotonous background of Amoxicillins due to its release form. After all, the drug is available in the form of dispersible tablets, which have many advantages compared to the pills we are used to.

In this article we will try to understand how Flemoxin differs from its analogues, and also clarify the positive aspects of the drug. And let’s not ignore the negative qualities, which, of course, are also present.

Astellas Pharma: new life for antibiotics

Astellas Pharma is the largest Japanese pharmaceutical concern. It appeared in 2005 thanks to the merger of two well-known Japanese companies: Fujisawa Pharmaceutical Co and Yamanouchi Pharmaceutical Co.

Today, Astellas Pharma works in various areas of medicine, creating both original drugs and analogues of well-known brands. The company also produces several antibiotics, which have become widely known due to their dispersible form.

Each of these medicines has an additional word in the name indicating a special form - solutab. Dispersible drugs include:

• cephalosporin antibiotic Ceforal solutab;
• Unidox Solutab, widely known in Russia;
• Vilprafen solutab;
• Flemoxin Solutab and Flemoklav Solutab are two related drugs containing Amoxicillin as the active ingredient.

I would like to note that Flemoxin Solutab is registered only in Germany, Iceland, Portugal and the CIS countries.

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Flemoxin solutab: composition of the drug

Flemoxin contains, as you already understood, the only active component - Amoxicillin - in the form of a stable compound (trihydrate).

Active ingredients

Levodopa
- benserazide

Release form, composition and packaging

Madopar "125"

Capsules hard gelatin, size No. 2, with an opaque pinkish-flesh body and an opaque light blue cap, marked “ROCHE” in black; the contents of the capsules are fine granular powder, sometimes clumped, light beige in color.

Excipients: microcrystalline cellulose - 13.5 mg, talc - 6.5 mg, - 1 mg, magnesium stearate - 0.5 mg.

Composition of the capsule cap: indigo carmine dye (E132) - 0.01 mg, titanium dioxide (E171) - 0.5 mg, gelatin - 21 mg.
Composition of the capsule body: red iron oxide dye (E172) - 0.03 mg, titanium dioxide (E171) - 1.12 mg, gelatin - 31.2 mg.

Madopar gss "125"

Modified-release capsules hard gelatin, size No. 1, with an opaque light blue body and an opaque dark green cap, with the inscription “ROCHE” in rusty red; the contents of the capsules are a fine granular powder, sometimes clumped, white or slightly yellowish in color.

Excipients: hypromellose - 115 mg, hydrogenated vegetable oil - 30 mg, calcium hydrogen phosphate - 27.5 mg, - 18 mg, povidone - 6 mg, talc - 10 mg, magnesium stearate - 5 mg.

Composition of the capsule cap: indigo carmine dye (E132) - 0.09 mg, iron oxide yellow dye (E172) - 0.53 mg, titanium dioxide (E171) - 0.31 mg, gelatin - 25.3 mg.
Composition of the capsule body: dye (E132) - 0.02 mg, titanium dioxide (E171) - 0.92 mg, gelatin - 38.3 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

Madopar fast-acting tablets (dispersible) "125"

Dispersible tablets white or almost white, cylindrical, flat on both sides, beveled, odorless or slightly odorless, slightly marbled, engraved with "ROCHE 125" on one side and a break line on the other; tablet diameter is about 11 mm, thickness is about 4.2 mm.

Excipients: anhydrous citric acid - 20 mg, pregelatinized corn starch - 41.5 mg, microcrystalline cellulose - 303 mg, magnesium stearate - 7 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

Madopar "250"

Pills pale red with small inclusions, cylindrical, flat, with a beveled edge, with a cross mark, engraved "ROCHE" and a hexagon on one side, with a cross mark on the other side; tablet diameter 12.6-13.4 mm, thickness 3-4 mm.

Excipients: mannitol - 103.2 mg, calcium hydrogen phosphate - 100 mg, microcrystalline cellulose - 38.6 mg, pregelatinized corn starch - 20 mg, crospovidone - 20 mg, ethylcellulose - 3 mg, red iron oxide dye - 1.5 mg, colloidal anhydrous silicon dioxide - 1 mg, docusate sodium - 0.2 mg, magnesium stearate - 5.5 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

pharmachologic effect

A combined antiparkinsonian drug containing a precursor and an inhibitor of peripheral decarboxylases.

In Parkinsonism, the brain neurotransmitter dopamine is produced in insufficient quantities in the basal ganglia. Levodopa, or L-DOPA - (3,4-dihydrophenylalanine), is a metabolic precursor of dopamine and, unlike the latter, penetrates well through the BBB. After levodopa enters the central nervous system, it is converted to dopamine by aromatic acid decarboxylase.

Parkinson's disease

Following oral administration, levodopa is rapidly decarboxylated to dopamine in both cerebral and extracerebral tissues. As a result, most of the administered levodopa does not reach the basal ganglia, and peripheral dopamine often causes adverse reactions. Therefore, blocking extracerebral decarboxylation of levodopa is necessary. This is achieved by simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.

Madopar is a combination of these substances in a 4:1 ratio, which is optimal and has the same effectiveness as levodopa in high doses.

Fast-acting (dispersible) tablets are especially indicated for patients with dysphagia, as well as patients who need a faster onset of action of the drug.

GSS capsules are a special dosage form with a delayed release of active substances in the stomach. The maximum concentration is 20-30% less than when taking Madopar "125" capsules and Madopar "250" tablets, and is achieved 3 hours after administration.

Restless legs syndrome

The exact mechanism of restless legs syndrome is unknown, but the dopaminergic system plays an important role in the pathogenesis of this syndrome.

Pharmacokinetics

Suction

Madopar "125" capsules and Madopar "250" tablets. Levodopa and benserazide are absorbed primarily in the upper small intestine. Cmax of levodopa in plasma is achieved approximately 1 hour after administration. The absolute bioavailability of levodopa averages 98% (74-112%). Madopar capsules and tablets are bioequivalent.

Cmax and AUC of levodopa increase proportionally to the dose (in the levodopa dose range from 50 to 200 mg).

Eating reduces the rate and extent of absorption of levodopa. When Madopar is prescribed after a normal meal, the Cmax of levodopa in plasma is 30% less and is achieved later. The degree of absorption of levodopa is reduced by 15%.

Madopar fast-acting tablets (dispersible) "125". The pharmacokinetic profiles of levodopa after taking Madopar in this dosage form are similar to those after taking Madopar tablets and capsules, however, the time to reach Cmax tends to shorten. The absorption parameters of fast-acting tablets (dispersible) are less variable between patients than with conventional dosage forms.

Madopar GSS "125", k modified release capsules. Madopar GSS "125" has different pharmacokinetic properties than conventional and dispersible dosage forms. The active substances are released slowly in the stomach. Cmax in plasma is 20-30% less than that of conventional dosage forms and is achieved approximately 3 hours after administration. The dynamics of plasma concentration is characterized by a longer T1/2 than that of conventional dosage forms, which convincingly indicates a continuous modifiable release of active substances. The bioavailability of Madopar GSS "125" is 50-70% of the bioavailability of Madopar "125" capsules and Madopar "250" tablets and does not depend on food intake. Food intake does not affect the Cmax of levodopa, which is achieved 5 hours after taking Madopar GSS "125".

Distribution

Levodopa crosses the BBB via a saturable transport system. Does not bind to plasma proteins, V d is 57 l. The AUC of levodopa in cerebrospinal fluid is 12% of that in plasma.

Benserazide in therapeutic doses does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine and liver.

Metabolism

Levodopa is metabolized by two main pathways (decarboxylation and o-methylation) and two secondary pathways (transamination and oxidation).

Aromatic amino acid decarboxylase converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids.

COMT methylates levodopa to form 3-o-methyldopa. T1/2 of this main metabolite from plasma is 15-17 hours, and in patients receiving therapeutic doses of Madopar, its accumulation occurs.

Reduced peripheral decarboxylation of levodopa when coadministered with benserazide leads to higher plasma concentrations of levodopa and 3-o-methyldopa and lower plasma concentrations of catecholamines (dopamine, norepinephrine) and phenolcarboxylic acids (homovanillic acid, dihydrophenylacetic acid).

In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine, which is a potent inhibitor of aromatic amino acid decarboxylase.

Removal

Against the background of inhibition of peripheral decarboxylase, T1/2 of levodopa is about 1.5 hours. Plasma clearance of levodopa is about 430 ml/min.

Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly in urine - 64% and, to a lesser extent, in feces - 24%.

Pharmacokinetics in special clinical situations

There are no data on the pharmacokinetics of levodopa in patients with renal and hepatic impairment.

In elderly patients (65-78 years) with Parkinson's disease, T1/2 and AUC increase slightly (by approximately 25%), which is not a clinically significant change and does not require a change in dosage regimen.

Indications

Parkinson's disease, including:

• in patients with dysphagia, with akinesia in the early morning hours and in the afternoon, patients with the phenomena of “depletion of the effect of a single dose” or “increase in the latent period before the onset of the clinical effect of the drug” (Madopar “125” fast-acting tablets (dispersible));
• in patients with any type of fluctuation in the action of levodopa, namely, “peak dose dyskinesia” and “end dose phenomenon”, for example, immobility at night (Madopar GSS "125").

Restless legs syndrome:

• idiopathic restless legs syndrome;
• restless legs syndrome in patients with chronic renal failure on dialysis.

Contraindications

• decompensated dysfunction of the endocrine system organs;
• decompensated liver dysfunction;
• decompensated renal dysfunction (except for patients with restless legs syndrome receiving dialysis);
• diseases of the cardiovascular system in the stage of decompensation;
• mental illness with a psychotic component;
• angle-closure glaucoma;
• simultaneous use with non-selective MAO inhibitors, a combination of MAO type A and MAO type B inhibitors;
• age up to 25 years;
• women of childbearing age who do not use reliable methods of contraception;
• pregnancy;
• lactation period (breastfeeding);
• hypersensitivity to the components of the drug.

Dosage

Treatment should be started gradually, with individual doses adjusted until the optimal therapeutic effect is achieved.

Madopar "125" capsules should be swallowed whole without chewing.

Madopar GSS "125" capsules should be swallowed whole without chewing; they should not be opened before use to avoid loss of the modified release effect of the active substance.

Madopar "250" tablets can be crushed to make them easier to swallow.

Madopar "125" fast-acting tablets (dispersible) should be dissolved in 25-50 ml of water. The tablet completely dissolves in a few minutes to form a milky-white solution, which should be taken no later than 30 minutes after the tablet dissolves. Since a precipitate can quickly form, it is recommended to stir the solution before use.

Parkinson's disease

Standard dosage regimen

Orally, at least 30 minutes before or 1 hour after meals.

Initial therapy

At the early stage of Parkinson's disease, it is recommended to begin treatment with Madopar at a dose of 62.5 mg (50 mg levodopa + 12.5 mg benserazide 3-4 times a day). If well tolerated, the dose should be gradually increased, depending on the patient's response.

The optimal effect is achieved, as a rule, with a daily dose containing 300-800 mg of levodopa + 75-200 mg of benserazide, taken in 3 or more doses. It may take 4 to 6 weeks to achieve optimal results. Further increases in the daily dose, if necessary, should be carried out at intervals of 1 month.

Maintenance therapy

The average maintenance dose is 125 mg (100 mg levodopa + 25 mg benserazide) Madopar 3-6 times a day. The frequency of administration (at least 3 times) during the day should be distributed so as to ensure optimal effect. To optimize the effect, it may be necessary to replace Madopar "125" in the form of regular capsules and Madopar "250" in the form of regular tablets with Madopar "125" fast-acting tablets (dispersible) or Madopar GSS "125".

Restless legs syndrome

The drug should be taken 1 hour before bedtime, with a small amount of food. The maximum daily dose is 500 mg Madopar (400 mg levodopa + 100 mg benserazide).

Idiopathic restless legs syndrome with sleep disturbances

The initial dose is 62.5-125 mg. If the effect is insufficient, the dose of Madopar should be increased to 250 mg (200 mg levodopa + 50 mg benserazide).

Idiopathic restless legs syndrome with sleep and sleep disorders

The initial dose is 1 capsule of Madopar GSS "125" and 1 capsule of Madopar "125" 1 hour before bedtime. If the effect is insufficient, the dose of Madopar GSS "125" should be increased to 250 mg (2 capsules).

Idiopathic restless legs syndrome with difficulty falling asleep and staying asleep, as well as disturbances during the day

Additionally: 1 dispersible tablet or 1 capsule of Madopar "125", the maximum daily dose of Madopar is 500 mg (400 mg of levodopa and 100 mg of benserazide).

Restless legs syndrome in patients with chronic renal failure receiving dialysis

The drug is prescribed in a dose of 125 mg (1 dispersible tablet or 1 capsule of Madopar "125") 30 minutes before the start of dialysis.

Dosage regimen in special cases

Parkinson's disease

Madopar can be combined with other antiparkinsonian drugs. However, as treatment continues, it may be necessary to reduce the dose of other drugs or gradually discontinue them.

Madopar "125" fast-acting tablets (dispersible) - a special dosage form for patients with dysphagia or akinesia in the early morning hours and in the afternoon or for patients with the phenomenon of "depletion of the effect of a single dose" or "increase in the latent period before the onset of the clinical effect of the drug" .

If during the day the patient experiences strong motor fluctuations (the phenomenon of “exhaustion of the effect of a single dose”, the phenomenon of “on-off”), it is recommended either more frequent administration of correspondingly smaller single doses, or, which is preferable, the use of Madopar GSS “125”.

It is best to switch to Madopar GSS "125" from one day to the next, starting with the morning dose. You should keep the same daily dose and dosage regimen as when taking Madopar "125" and Madopar "250".

After 2-3 days, the dose is gradually increased by approximately 50%. Patients should be warned that their condition may temporarily worsen. Due to the characteristics of the dosage form, Madopar GSS "125" begins to act a little later.

The clinical effect can be achieved faster by prescribing Madopar GSS "125" together with Madopar "125" capsules or Madopar "125" fast-acting tablets (dispersible). This may be optimal as the first morning dose, which should be slightly higher than subsequent doses.

The dose of Madopar GSS "125" should be adjusted slowly and carefully, and the interval between dose changes should be at least 2-3 days.

In patients with symptoms of the disease that manifest themselves at night, a positive effect was achieved by gradually increasing the evening dose of Madopar GSS "125" to 250 mg (2 capsules) before bedtime.

With a pronounced effect of Madopar GSS "125" (dyskinesia), increasing the intervals between doses is more effective than reducing the single dose.

If Madopar GSS "125" is not effective enough, then it is recommended to return to the previously used treatment with Madopar "125", Madopar "250" or Madopar "125" fast-acting tablets (dispersible).

With long-term therapy, episodes of “freezing”, “exhaustion phenomenon” and the “on-off” phenomenon may occur. In case of episodes of “freezing”, “exhaustion phenomenon”, the dose of the drug is divided (reducing the single dose or shortening the interval between doses of the drug), and when the “on-off” phenomenon occurs, the single dose is increased with a decrease in the number of doses. Subsequently, you can try to increase the dose again to enhance the effectiveness of treatment.

U patients with mild or moderate renal impairment no dose adjustment is required. Madopar is well tolerated patients receiving hemodialysis sessions.

Restless legs syndrome

To avoid an increase in the symptoms of restless legs syndrome (early appearance during the day, increasing severity and involvement of other parts of the body), the daily dose should not exceed the recommended maximum dose of Madopar - 500 mg (400 mg levodopa + 100 mg benserazide).

If clinical symptoms increase, the dose of levodopa should be reduced or levodopa should be gradually discontinued and other therapy should be prescribed.

Side effects

From the central nervous system and peripheral nervous system: agitation, anxiety, insomnia, hallucinations, delirium, temporary disorientation (especially in elderly patients and in patients with a history of these symptoms), depression, headache, dizziness, and in later stages of treatment sometimes spontaneous movements (such as chorea or athetosis), episodes of “freezing”, weakening of the effect towards the end of the dose period (the “exhaustion” phenomenon), the “on-off” phenomenon, severe drowsiness, episodes of sudden drowsiness, increased manifestations of restless legs syndrome.

From the digestive system: nausea, vomiting, diarrhea; in some cases - loss or change in taste, dryness of the oral mucosa.

From the cardiovascular system: arrhythmias, orthostatic hypotension (weakens after reducing the dose of Madopar), arterial hypertension.

From the respiratory system: rhinitis, bronchitis.

From the hematopoietic system: rarely - hemolytic anemia, transient leukopenia, thrombocytopenia.

Dermatological reactions: rarely - itching, rash.

From the laboratory parameters: sometimes - a transient increase in the activity of liver transaminases, alkaline phosphatase, an increase in gamma-glutamyl transpeptidase, an increase in blood urea nitrogen, a change in the color of urine to red, darkening when standing.

From the body as a whole: anorexia.

Others: febrile infection.

Overdose

Symptoms: increased manifestations of side effects - arrhythmia, confusion, insomnia, nausea and vomiting, pathological involuntary movements. When taking a dosage form with a modified release of active substances (Madopar GSS "125") in the stomach, the onset of symptoms may be delayed.

Treatment: symptomatic therapy - respiratory analeptics, antiarrhythmic drugs, neuroleptics; it is necessary to monitor vital functions. When using a dosage form with a modified release of active substances (Madopar GSS "125"), further absorption of the drug should be prevented.

Drug interactions

Pharmacokinetic interaction

When used concomitantly, trihexyphenidyl (an anticholinergic drug) reduces the rate, but not the extent, of absorption of levodopa. The administration of trihexyphenidyl together with Madopar GSS "125" does not affect the pharmacokinetics of levodopa.

When antacids are used simultaneously with Madopar GSS, the degree of absorption of levodopa is reduced by 32%.

Ferrous sulfate reduces Cmax in blood plasma and the AUC value of levodopa by 30-50%; these changes are in some cases clinically significant.

Metoclopramide increases the rate of absorption of levodopa.

Levodopa does not interact pharmacokinetically with bromocriptine, amantadine, selegiline and domperidone.

Pharmacodynamic interaction

Neuroleptics, opiates and those containing reserpine suppress the effect of Madopar.

If it is necessary to prescribe Madopar to patients receiving irreversible non-selective MAO inhibitors, at least 2 weeks must pass from the moment of stopping the MAO inhibitor before starting to take Madopar.

Selective MAO type B inhibitors (including selegiline, rasagiline) and selective MAO type A inhibitors (moclobemide) can be prescribed during treatment with Madopar. It is recommended to adjust the dose of levodopa depending on the patient's individual needs in terms of effectiveness and tolerability. The combination of MAO type A and MAO type B inhibitors is equivalent to taking a non-selective MAO inhibitor, therefore such a combination should not be prescribed simultaneously with Madopar.

Madopar should not be prescribed simultaneously with sympathomimetics (adrenaline, norepinephrine, isoproterenol, amphetamine), since levodopa can potentiate their effect. If concomitant use is necessary, carefully monitor the cardiovascular system and, if necessary, reduce the dose of sympathomimetics.

The combined use of the drug with other antiparkinsonian drugs (anticholinergics, amantadine, dopamine agonists) is possible, and not only the desired but also the undesirable effects may be enhanced. It may be necessary to reduce the dose of Madopar or another drug.

When using Madopar simultaneously with a COMT inhibitor, it may be necessary to reduce the dose of Madopar. If treatment with Madopar is started, anticholinergic drugs should not be discontinued abruptly, since levodopa does not take effect immediately.

Since a patient receiving Madopar may experience fluctuations in blood pressure and arrhythmias during halothane anesthesia, Madopar should be discontinued 12-48 hours before surgery.

Levodopa may affect laboratory results of catecholamines, creatinine, uric acid and glucose, and a false-positive Coombs test result is possible.

In patients receiving Madopar, taking the drug simultaneously with a protein-rich meal may interfere with the absorption of levodopa from the gastrointestinal tract.

special instructions

Persons with hypersensitivity to the drug may develop corresponding reactions.

Adverse reactions from the digestive system, possible at the initial stage of treatment, are largely eliminated if Madopar is taken with a small amount of food or liquid, as well as by slowly increasing the dose.

Patients with open-angle glaucoma should have their intraocular pressure measured regularly because levodopa may theoretically increase intraocular pressure.

Patients with diabetes mellitus should frequently monitor blood glucose levels and adjust the dose of hypoglycemic drugs.

If possible, Madopar should be continued for as long as possible before general anesthesia, with the exception of halothane anesthesia. Since fluctuations in blood pressure and arrhythmias may occur in a patient receiving Madopar during halothane anesthesia, Madopar should be discontinued 12-48 hours before surgery. After surgery, treatment is resumed, gradually increasing the dose to the previous level.

Madopar cannot be canceled abruptly. Abrupt discontinuation of the drug can lead to the development of neuroleptic malignant syndrome (fever, muscle rigidity, as well as possible mental changes and increased serum CPK), which can take a life-threatening form. If such symptoms occur, the patient should be under medical supervision (hospitalization if necessary) and receive appropriate symptomatic therapy, which may include re-prescribing Madopar after an appropriate assessment of the patient's condition.

Depression can be a clinical manifestation of the underlying disease (parkinsonism, restless legs syndrome) and can also occur during Madopar therapy. Patients taking Madopar should be closely monitored for the possible occurrence of psychiatric adverse reactions.

Some patients with Parkinson's disease have experienced the appearance of behavioral and cognitive disorders as a result of uncontrolled use of increasing doses of the drug, despite the doctor's recommendations and significantly exceeding therapeutic doses of the drug.

Impact on the ability to drive vehicles and operate machinery

If drowsiness or sudden episodes of drowsiness occur, the patient should stop driving a car or working with machines and mechanisms. If these symptoms occur, dose reduction or discontinuation of therapy should be considered.

Pregnancy and lactation

Madopar is contraindicated during pregnancy and women of childbearing age who do not use reliable methods of contraception, due to possible disruption of skeletal development in the fetus.

If pregnancy occurs during treatment with Madopar, the drug should be discontinued immediately in accordance with the recommendations of the attending physician.

It is not known whether benserazide is excreted in breast milk. If it is necessary to use Madopar during lactation, breastfeeding should be stopped, since skeletal development disorders in the child cannot be ruled out.

Use in childhood

Contraindication: age under 25 years.

Madopar "125" fast-acting tablets (dispersible) should be stored at a temperature not exceeding 25°C. Shelf life - 3 years.

Madopar "250" tablets should be stored in a dry place at a temperature not exceeding 25°C. Shelf life - 4 years.

The drug should be stored out of the reach of children.

Field of activity (technology) to which the described invention relates

The present invention relates to a water-dispersible tablet composition that includes a therapeutically active compound.

DETAILED DESCRIPTION OF THE INVENTION

Therapeutically active compounds or drugs are often administered to patients in the form of a tablet, in the case where the drug is intended for oral administration, since tablets are a particularly convenient pharmaceutical form for production, storage and use. However, if these tablets are administered to patients who may have difficulty swallowing tablets (such as children or more seriously ill patients), problems may arise, especially when taking large tablet sizes due to large amounts of medication. , which should be contained in each of the tablets. A solution to such problems would be to provide such a composition in tablet form that is capable of dispersing in water to form a dispersion comprising the drug, which can then be consumed by the patient.

Known water-dispersible tablets include foaming compositions that produce gas, resulting in rapid tablet disintegration, but their production is expensive and requires strict manufacturing regulations; other known water-dispersible tablets use disintegrating agents, particularly microcrystalline cellulose, which is part of the dispersible tablets of the drug "Felden R". The present inventors have tested well-known disintegrants (both internally and externally applied to preformed granules), in particular sodium starch glycolate (for example, Explotab), structured povidone (for example, Kollidon CL) and structured sodium carboxymethylcellulose (eg Starch, Avicel PH 102 and Ac-Di-Sol products) in acyclovir tablet, but have been found to consist of a composition that does not have satisfactory water dispersibility. In addition, the authors of the present invention tested an ion exchange resin (Amberlite I RP88) as a disintegrating agent and in order to increase the wettability of the tablet with water, to enhance the penetration of water into it during the dispersion process, the authors introduced surfactants [for example, sodium lauryl sulfate and sodium decusate ], but in all of them the duration of disintegration turned out to be significant.

After lengthy searches and studies, the inventors have now found that the use of a swellable composition within the granulate for the manufacture of a tablet makes it possible to obtain a tablet that has good dispersibility in water, forming a dispersion that the patient can drink.

Swelling clays such as Wiggum and other magnesium aluminum silicates have previously been studied and proposed for use as disintegrants, fillers and lubricants in the manufacture of swellable and water-dispersible tablets [Rubenstein, Pharmaceutics - The Science of Dosage Form Design (1990), see disintegrators on p. 312 and 314]. Moreover, there is no suggestion that clay would be suitable to meet the more stringent requirements for dispersible tablets. For swelling tablets, it is only necessary that the disintegration time in water be less than 15 minutes and that when disintegrated in water they form particles that pass through a 2.00 mm sieve [British Standard Pharmacopoeia Test for Swellable Tablets] . Such long disintegration times and large particle sizes are completely unacceptable for dispersible tablets.

Even when swelling clays are offered as disintegrating agents for tablet swelling, they are not considered very suitable for this application because, due to their off-white color, they often alter the color of the tablet and are less effective than other disintegrating agents [Banker and Anderson - Theory and Practice of Industrial Pharmacy p. 328 (1986) and Bhargwa et al. Drug Development and Industrial Pharmacy 17(15), 2003-2102 (1991)]. In fact, of the ten disintegrating agents that are listed by Marshall and Rudnick in Nioderb Pharmaceutics (1990), p. 374, bentonite is the least swelling. In the above references to textbooks there is no mention of how the swelling clay should be introduced, that is, injected into the granule or outside the granule. In the first case, the clay should be added to the mixture from which the granulate is formed, and in the latter case, the clay should be added to the pre-formed granulate.

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The journal reviewed the following work relating to swelling clays, particularly the products Wiggum and bentonite, as disintegrants: Way et al. J. Pharm. Sci., 55, 1215 (1966); Granberg et al., J Am. Pharm. Assoc. Sci, 38, 648 (1949); Gross et al., J. Am Pharm. Assoc. Sci, 41, 157 (1952); Firouzabadian et al., J. Am Pharm. Assoc. Sci, 43, 248 (1954); Ward et al., Drug Cosmetic Ind, 91, 35 (1962); Nair et al., J. Am. Pharm. Assoc. Sci, 46, 131 (1957) and Patel et al., Indian J. Pharm., 19 Jan. 1957 Way et al. then compared three grades of Wiggum products, evaluating both extragranular and intragranular additions, and concluded that "the clays were not good disintegrants in the case of wet granulation" (i.e. intragranular addition) , as a result of which they recommended extragranular addition. Moreover, on p. 19 in the work of employees of the company "R. T. Vanderbilt and Co" (manufacturer of Wigam products) entitled "Wigam - a universal component for pharmaceutical compositions" a description of the composition of the tablet, to which the Wiggam product is added after granulation (tablet NO.2) . This publication does not make any reference to the tablet formulation to which Wigam is added during the granulation process.

In contrast to the above recommendations, the present inventors have found that in order to meet the requirements of the British Pharmacopoeia (BP) standard for dispersible tablets (currently specified dispersion time is 3 minutes or less), swelling clay, in particular the Wigam product, should be added during the granulation process . In the same case, when the swelling clay is added only after granulation, the duration of dispersion is too long to meet the requirements of the above standard.

The use of Wigam and other swelling clays as described above has enabled the present inventors to prepare water-dispersible tablets that contain various therapeutically active compounds. The resulting tablets can be easily dispersed in water to form a dispersion that can be easily consumed by the patient.

The present invention provides a water-dispersible tablet comprising a therapeutically active compound selected from the class consisting of an analgesic propionic acid derivative, an anxiolytic benzodiazepine, an activating nucleoside derivative (e.g., acyclovir), a petroquinone antiprotozoan, allopurinol, oxopurinol, an anticonvulsant 1,2,4-triazine derivative (eg, lamotrigine) and trimethoprim (possibly in combination with sulfamethoxazole), together with an effective amount of a pharmaceutically acceptable swelling clay to produce a tablet that is capable of dispersing in water within a 3-minute period of time to form a dispersion capable of passing through a 710 µm sieve, which complies with the dispersible tablet testing standards as defined by British Pharmacopocia, 1988, Tau 11, p. 895.

The above therapeutically active compound used in the tablet according to the present invention is hereinafter referred to as the "active compound".

The present invention further provides a method of preparing a water-dispersible tablet which includes a therapeutically active compound selected from the class consisting of an analgesic propionic acid derivative, an anxiolytic benzodiazepine, an antiviral nucleoside derivative, a naphthoquinone antiprotozoan, allopurinol, oxopurinol, an anticonvulsant 1,2,4-triazine derivative, and trimethoprim (optionally in combination with sulfamethoxazole), together with an effective amount of a pharmaceutically acceptable swelling clay, wherein said active compound is combined with said clay to form a water-dispersible tablet that is dispersible in water for a 3-minute period of time to form a dispersion that is capable of passing through a 710 µm sieve, consistent with the Dispersible Tablet Test Method as defined by the British Pharmacopoeia 1988, Vol. 11, p. 895.

Preferably, said method includes the steps of:

A) mixing, in a dry, finely divided state, the active compound with an effective amount of a pharmaceutically acceptable swellable clay, optionally with the addition of one or more other pharmaceutical excipients or bases for the preparation of a medicament;

B) adding a pharmaceutically acceptable liquid in an amount sufficient to wet the dry mixture;

C) granulating the resulting wet mixture to form granules;

D) drying the granules and optionally mixing these granules with other possible excipients or bases for the preparation of drugs, in particular lubricants, glidants, flavoring agents and disintegrating agents;

E) compressing the granules to form a tablet that is capable of dispersing in water over a 3-minute period of time to form a dispersion that is capable of passing through a 710 µm sieve, which corresponds to the British Pharmacopoeia test for dispersible tablets.

In addition to the speed of dispersion in water, the tablets of the present invention have the additional advantage that they satisfy the British Pharmacopoeia (BP) test requirements for dispersible tablets with respect to dispersion time and quality of dispersions (that is, the latter passes through sieve with mesh size 710 microns).

Preferably, the duration of tablet dispersion in accordance with the present invention should be less than 2 minutes, more preferably less than about 1.50 minutes, and most preferably less than about 1 minute.

An additional advantage of the tablets of the present invention is that, by forming a relatively fine dispersion, the dissolution time of the tablet is reduced, so that the drug can be absorbed into the bloodstream at a much faster rate. In addition, the short duration of dispersion and the relatively thin dispersions that form the tablets of the present invention are also advantages for swallowable tablets. In accordance with the present invention, tablets can thus be designed both for dispersion in water and for direct swallowing. Tablets which are intended to swell according to the present invention should preferably be provided with a film coating which facilitates swallowing. However, the dispersion time of such film-coated tablets increases to 5 minutes, as determined in accordance with the above-mentioned BF test.

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The present invention further provides a dispersible film-coated tablet comprising a therapeutically active compound selected from the class comprising analgesic propionic acid derivative, anxiolytic benzodiazepine, antiviral nucleoside, naphthoquinone antiprotozoan allopurinol, oxopurinol, anticonvulsant 1,2, A 4-triazine derivative and trimethoprim (optionally in combination with sulfomethoxazole) together with an effective amount of a pharmaceutically acceptable swelling clay to provide a film-coated tablet that is capable of dispersing in water to form a dispersion capable of passing through a 710 µm sieve, which corresponds to the British Pharmacopoeia test for dispersible tablets, where the specified period of time during the test varies from 3 to 5 minutes. This selected specification contains references to tablets that refer to tablets both with and without film coatings.

After passing the dispersion through a 710 µm sieve, there should be virtually no residue remaining except for fragments of undissolved coating or tablet shell which remain on the sieve or adhere to the undersurface of the disk, if such a disk has been used, in which case any remains. any residue, it must be a soft mass containing no tangible solid core that has not been wetted.

The particle size distribution in the dispersion, especially when the active compound is acyclovir, is given in table. 1, and the increase in preference for values ​​is presented in the direction from left to right.

Such tablets may be film coated, for example with hydroxypropyl methylcellulose, polyethylene glycol or titanium dioxide, and/or scored, and/or polished, for example with polyethylene glycol 8000. If the tablets are film coated, this allows for ease of use. swallowing or chewing (that is, the tablets are acceptable either for dispersing in water or for direct swallowing or chewing), but the duration of dispersion is increased.

The present invention also provides:

A) granules containing the active substance and a pharmaceutically acceptable swelling clay suitable for use in the manufacture of a water-dispersible tablet according to the present invention;

B) using granules as defined above in the manufacture of a water-dispersible tablet according to the present invention; after granulation and before pressing, it is possible to add an additional amount of swelling clay;

C) using a pharmaceutically acceptable swellable clay as a dispersing agent in the manufacture of a water-dispersible tablet containing the active substance (as defined above);

D) use in human medical therapy of a water-dispersible tablet that includes an active substance (as defined above) together with an effective amount of a pharmaceutically acceptable swellable clay within the granules of the tablet.

A suitable swelling clay of the present invention is a pharmaceutically acceptable crystalline mineral compound, particularly aluminum magnesium silicate (eg, Wiggam product).

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The therapeutic use of the tablet of the present invention includes both treatment and prevention.

It has been found that the present invention can be used in a particular application in combination with lamotrigine due to the instability of lamotrigine over a long period of time in water. Moreover, dispersible tablets containing lamotrigine have been found to form a finer dispersion than tablets containing more conventional disintegrating agents, particularly the Explotab product.

Additional aspects of the present invention illustrated in relation to lamotrigine are listed below:

E) granules suitable for use in the manufacture of a water-dispersible compressed tablet comprising lamotrigine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent;

F) using granules as defined above in the manufacture of a water-dispersible compressed tablet, wherein it is possible to add additional crystalline mineral clay component after granulation and before compression;

G) using a pharmaceutically acceptable crystalline mineral clay as a dispersing agent in the preparation of a water-dispersible compressed tablet containing lamotrigine or a pharmaceutically acceptable salt thereof;

H) water-dispersible tablets comprising lamotrigine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable crystalline mineral clay with a lattice structure that expands upon hydration as a dispersing agent; lamotrigine or its pharmaceutically acceptable salt together with mineral clay is contained within the tablet in granular form;

I) A method for the manufacture of lamotrigine water-dispersible tablet, which involves the steps of:

Dry mixing in finely divided form lamotrigine or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable crystalline mineral clay, which can be selected from the class comprising attapulgite, smectite and montmorillonoid clays or magnesium aluminosilicate;

Possible addition of other pharmaceutical components, in particular excipients (for example, lactose, Avicel or mannitol), disintegrants, binders and the like;

Adding an amount of pharmaceutically acceptable liquid sufficient to wet the mixture;

Granulation of the resulting wet mass;

Drying the granules and mixing the granules with possible lubricants, glidants, flavoring agents, disintegrating agents and the like, forming the mixture into tablets;

J) use in human medicine of a water-dispersible compressed tablet comprising lamotrigine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent;

K) a method of treating a person for disorders of the central nervous system, which involves administering to the body a water-dispersible compressed tablet comprising lamotrigine or a pharmaceutically acceptable sorrel thereof together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent.

Particularly preferred tablets are those containing lamotrigine as a base.

The above tablets can be used in human medicine in the treatment of disorders of the central nervous system, in particular in the treatment of epileptic attacks. They may be taken one or more times per day, for example up to five times per day, at the discretion of the attending physician and depending on the age and condition of the patient, especially depending on the disease to be treated, the selected dosage unit and the total dose required. An acceptable daily dose for the treatment of epileptic seizures is usually in the range of 5 - 500 mg, usually in the range of 25 - 400 mg, based on the active base.

It is desirable that the physical dimensions of said tablets be such that they can be dispersed in a reasonably small volume of water before swallowing. Thus, for example, a tablet containing 5 mg (based on the active base) of lamotrigine or its salt, a dose that is particularly suitable for pediatric use, must be small enough to be dispersed in a volume of water that can be held by a standard 5 ml medical spoon.

It is very advantageous when the tablets of the present invention containing lamotrigine (or a salt thereof) include magnesium aluminosilicate, in particular the product "Wigam F", as a swelling clay together with additional possible pharmaceutical excipients or drug components listed above, for example with binder compositions , lubricating additives, fillers, disintegrants and the like.

Successful results are achieved when such tablets contain these components in the following proportions: lamotrigine 2 - 90 wt.%, preferably 5 - 40 wt.%; swelling clay 0.25 - 40 wt.%, preferably 0.25 - 10 wt.%.

Below is a possible suitable formulation of a dispersible tablet containing 25 to 200 mg of lamotrigine.

Lamotrigine 30 - 50 wt.%, preferably 35 - 45 wt.%.

Calcium carbonate 26 - 46 wt.%, preferably 31 - 41 wt.%.

LHPC-LHII or microcrystalline cellulose (for example, the product "Avicel PH 101") 5 - 30 wt.%, preferably 5 - 15 wt.%.

Magnesium aluminosilicate (Wigam F product or bentonite) 0.25 - 30 wt.%, preferably 0.25 - 10 wt.%.

Povidone - from 0.25 to 5.0 wt.%, preferably 0.5 to 2 wt.%, or
Starch, swelling in cold water, 1.0 - 8.0 wt.%, preferably 2 - 5 wt.%.

Sodium starch glycolate 0 - 8 wt.%, preferably 0 - 5 wt.%.

Magnesium stearate 0.25 - 2 wt.%. preferably 0.25 - 1 wt.% and, if possible, equipped with a film coating of: Opadry product 0.1 - 2 wt. %, preferably 0.25 - 1 wt.% polyethylene glycol 8000 - 0.1 to 0.5 wt. %, preferably 0.1 - 0.2 wt.%.

Below is a possible acceptable composition of a dispersible tablet containing 5 - 50 mg of lamotrigine (concentration of components expressed in wt.%): lamotrigine 3 - 13, preferably 5 - 11; lactose or calcium carbonate 50 - 60, preferably 53 - 69; microcrystalline cellulose (for example, the product "Avicel PH101") or LHPC-LHII 20 - 35, preferably 24 - 30; sodium starch glycolate 0 - 8, preferably 0 - 5; magnesium aluminosilicate (Wigam F product or bentonite) - 0.25 - 30, preferably 0.25 - 10; povidone K30 0.25 - 5.0, preferably 0.5 - 2.0, or cold water swelling starch 1.0 - 8.0, preferably 2 - 5; docusate sodium 0 - 0.5, preferably 0.5 - 0.15; sodium saccharin 0 - 3, preferably 0.5 - 2; magnesium stearate 0.25 - 2, preferably 0.25 - 1 and, if possible, provided with a film coating of: Opadry product 0.1 - 2.0 preferably 0.25 - 1 polyethylene glycol 8000 0.1 - 0.5 , preferably 0.1 - 0.2.

As stated above, the present invention is particularly suitable for a water-dispersible tablet composition which contains acyclovir as an active ingredient.

Acyclovir is a compound that has been found to have potent activity against viruses of the herpes family, especially herpes simplex and Lerpes varicella zoster. This action has been demonstrated by the remarkable success of acyclovir in the therapeutic treatment of a clinical condition, in particular in the treatment of genital herpes caused by the Lerpes varicella zoster virus.

In the treatment of certain diseases, it may be necessary to administer relatively large doses of acyclovir to the patient to achieve effective therapeutic plasma drug levels, particularly when oral administration is desired. For example, when treating shingles, acyclovir is recommended to be administered into the body in 800-milligram dosages five times a day. Tablet formulations containing 800 mg of acyclovir are now available, but the relatively large tablet size can sometimes make it difficult for elderly patients to swallow, and these patients are particularly susceptible to herpes zoster. This problem is solved by the water-dispersible tablets of the present invention, which allow relatively large doses of acyclovir to be administered to the body as a dispersion for drinking by the oral route.

The water dispersibility benefits of tablets of the present invention containing acyclovir as an active ingredient are particularly surprising given the poor water dispersibility exhibited by tablets that contain conventional disintegrants, particularly sodium starch glycolate, cross-linked povidone and cross-linked sodium carboxymethylcellulose.

However, with respect to acyclovir, the present invention has the following additional aspects:

I) granulate comprising acyclovir together with a pharmaceutically acceptable magnesium aluminosilicate compound;

M) using the granulate in accordance with item e) above in the preparation of a water-dispersible tablet composition;

N) the use of magnesium aluminosilicate in the process of preparing a water-dispersible tablet composition with acyclovir;

O) a water-dispersible pharmaceutical tablet composition comprising acyclovir together with a pharmaceutically acceptable magnesium aluminosilicate compound;

P) a method for preparing a pharmaceutical tablet composition, which involves mixing acyclovir with a magnesium aluminosilicate compound and, possibly, one or more additional pharmaceutical excipients or drug components: granulating the resulting mixture together with a pharmaceutically acceptable liquid; drying the prepared granulate; optionally mixing the dried granulate with one or more additional pharmaceutical excipients or drug components and then compressing the dried granulate into tablets; the liquid used in the above granulation step is preferably an aqueous liquid, for example an aqueous ethanol mixture; the finished tablets can further be coated with a film, for example hydroxypropyl methylcellulose, titanium dioxide or polyethylene glycol and, if desired, polished, for example polyethylene glycol 8000.

It is advantageous when the tablets according to the present invention containing acyclovir include magnesium aluminosilicate, in particular the product "Wigam F", as a swelling clay, possibly together with additional pharmaceutical excipients or drug components mentioned above, in particular with disintegrating agents, binders, fillers, lubricants and the like.

It is useful when such tablets contain the components in the following proportions: acyclovir 40 - 98 wt.%, preferably 75 - 85 wt.%, swelling clay 0.5 - 40 wt.%, preferably 0.5 - 10 wt.%.

The following is a possible acceptable formulation of an acyclovir dispersible tablet containing 200 to 800 mg of acyclovir:

• acyclovir - from 70 to 90 wt.%, preferably 75 to 85 wt.%;
• povidone or starch, swelling in cold water, 0.25 - 5 wt.%, preferably 0.5 - 2 wt.%;
• magnesium aluminosilicate (Wigam F product or bentonite) 0.5 - 30 wt.%, preferably 0.5 - 10 wt.%;
• microcrystalline cellulose (product "Avisel PH101" or LHPC-LHII) 5 - 25 wt.%, preferably 5 - 15%;
• sodium starch glucolate 0 - 8 wt.%, preferably 0.5 wt.%;
• magnesium stearate 0.25 - 2 wt.%, preferably 0.25 - 1.0 wt.% and, if possible, film-coated with Opadry product 0.1 - 2 wt.%, preferably 0.25 - 1 .0 wt.%;
• polyethylene glycol 8000 0.1 - 0.5 wt.%, preferably 0.1 - 0.2 wt. %.

The essence of the invention is illustrated using the following examples (see tables 3 - 10). Examples 1 to 6 and 29 are comparative, while examples 7 to 28, 30 and 31 illustrate the processes for preparing tablets in accordance with the present invention, which contain acyclovir as an active substance.

In accordance with the present invention, to illustrate that the disintegration time remains constant across varying tablet hardnesses, the formulation of Example 7 was compressed with forces of approximately 8 lbs, 3629 kg (7a), 12 lbs, 5443 kg (7b) and 18 lbs, 8165 kg (7c); The results that were obtained are presented below.

Examples 32 - 40 illustrate the preparation of tablets in accordance with the present invention, in which the active substance is lamotrigine (see Tables 11 and 12).

Examples of tablet compositions, including other activating substances, are given in table. 13.

Method of receipt. The tablets presented in Examples 1-45 were prepared according to the following general method:

A) the dry mixture was prepared using all components except the product "Povidone" (polyvinylpyrrolidone K30, sodium docusate (if intended for this use) and magnesium stearate;

B) povidone/polyvinylpyrrolidone K30 and sodium docusate (if intended) were dissolved in a 50% aqueous alcohol solution to prepare a solution for granulation;

C) the granulation solution was added to the dry mixture to prepare the granules;

D) the wet granules were dried in a fluid bed dryer;

E) the granules were then sifted through a 1000 µm sieve;

F) the dried granules were mixed with magnesium stearate and compressed into tablets.

In the case of using aromatic (flavor) additives, they were introduced at the above mixing stage (f).

This general method is illustrated with respect to the following specific examples.

Example 8 (uncoated tablets):

A) the dry mixture was prepared using all components except povidone/polyvinylpyrrolidone K30 and magnesium stearate using a Diozna P100 (high shear mixer-granulator) for 3 minutes;

B) povidone/polyvinylpyrrolidone K30 was dissolved in a 50% aqueous alcohol solution to prepare a granulation solution;

C) the solution was added until an amount of approximately 300 ml was reached for each kilogram of the weight of the dry mixture for the preparation of granules. Dry mixing was carried out for approximately 5 minutes;

D) The wet granules were dried in an Aeromatic T3 fluidized bed dryer at 70°C for approximately 30 minutes. The moisture content of the granules was approximately 4%;

F) the dried granules were mixed with magnesium stearate using a collet mixer for approximately 10 minutes and subjected to compression into tablets using a Mainestry D3 rotary tablet machine, which was equipped with caplet-shaped punches approximately 19.3 mm long and 9.0 wide mm. The tablets were obtained by compression so that the weight of each was 1052 mg2%.

Such granules can be used to prepare dispersible tablets with other doses of acyclovir, for example 200 and 400 mg, by pressing the dried granules into tablets weighing 263 and 256 mg respectively using round punches whose diameters are 11.0 and 8.6 respectively mm.

Example 9 (film-coated tablet).

The implementation of steps a) to f), which are described in example 8, was repeated to obtain an uncoated tablet, which was then provided with a film coating in accordance with the following procedure.

For this purpose, a Mainestri Axellakota 10 film coating unit was used. The coating suspension was sprayed onto the tablet cores so that their weight gain was in the range of 0.5-1.0, subject to the following acceptable parameters:

• tray rotation speed - 8.5 rpm,
• material consumption when spraying - 20 g/min,
• inlet temperature - 75 o C,
• outlet temperature - 53 o C.

The film-coated tablets were then coated with a polishing coating of Polyethylene Glycol 8000 with an additional weight gain of 0.1-0.2%.

Examples from 13 - 15. In the experiment of Example 13, Acyclovir, Avisel pH101, sodium starch glycolate and Vigam F were dry mixed in a mixer. After adding a sufficient volume of 50% aqueous alcohol solution (IMS), the mixture was granulated. The prepared granules were dried, mixed with magnesium stearate, and then compressed to form tablets.

Example 14. The procedure outlined in Example 13 for preparing granules and forming tablets is carried out in its entirety, except that granulation of the dry mixture is carried out using Povidone in a 50% aqueous alcohol solution. Coating of molded tablets can be accomplished by treating the tablet with a dispersion of white Opadry in purified water and drying the coated tablets, which are then polished using a solution of polyethylene glycol 8000, USNF in 50% aqueous alcohol solution (IMS).

In the experiment of Example 15, the procedure set out in Example 13 for preparing granules and forming tablets was repeated in its entirety, except that the operation of granulating the dry mixture using Povidone in a 50% aqueous alcohol solution.

Example 33:

A) the dry mixture was prepared using all components except Povidone/polyvinylpyrrolidone K30 and magnesium stearate using a Morton mixer with c-blades by mixing at low speed for 10 minutes;

B) povidone/porlivinylpyrrolidone K30 was dissolved in a 50% aqueous alcohol solution, prepared for granulation;

D) wet mixing was carried out for approximately 10 minutes. The wet granules were sifted through a 2000 μm sieve;

E) the wet granules were dried in an Aeromatic fluid bed dryer at 70° C. for approximately 25 minutes;

F) the granules were then sifted through a 1000 µm sieve;

G) the dried granules were mixed with magnesium stearate using a Rotomixer rotary mixer for 5 minutes and subjected to compression into tablets using a Mainesti D3 rotary press equipped with round punches with a diameter of 5.6 mm (normal radius of curvature) dies. The tablets were compressed so that the weight of each of them was 62.55 mg2%.

At the above mixing stage g) flavoring agents may be added.

To make a 50 milligram tablet, the same procedure was followed, except that in this case a die with a diameter of 11.8 mm was used and the tablets were compressed so that each tablet weighed 625.5 mg 2%.

Lamotrigated tablets can be film-coated using the same procedure as described in Example 9.

Tablets prepared according to the above examples were then subjected to the following tests.

Tablet evaluation methods:

1. Average weight of tablets. Twenty tablets were weighed on an analytical balance and the average weight of the tablets was calculated.

2. Tensile strength of tablets (kilopounds, cf 454 kg). Five tablets were individually tested using a Schleiniger crush tester and the average tensile strength was calculated from the results.

3. Looseness (loses in percent). 10 tablets were accurately weighed and subjected to a 10-minute friability test using a Rocha friability tester. The tablets were dusted off, reweighed, and weight loss due to friability was calculated as a percentage of the initial weight loss.

4. Duration of dispersion disintegration of diesel fuel (BF 1988). 6 tablets were tested in accordance with the above BF procedure (without discs) for dispersible tablets. In this case, water with a temperature of 19-21 o C was used.

5. Quality of dispersion. In accordance with the test procedure for uniformity of RF dispersion for dispersible tablets (BF 1988, vol. 11, p. 895), two tablets were placed in 100 ml of water at a temperature of 19-21 o C and allowed to disperse. The result was a homogeneous dispersion that passed through a sieve with opening sizes of 710 μm.

Pellet evaluation methods:

1. Loss on drying (LOD). The residual moisture content of the granules (RMC) was determined using a 3-4 gram sample using a Computertrack moisture analyzer set at 90 o C and operating in accordance with the procedure specified by the manufacturer.

2. Weight average diameter (SVD). A 10-gram sample of granules was sieved for 2 minutes at acceptable pulsating amplitudes in an Allen Bradley sonic sifter according to the manufacturer's instructions. In this case, sieves with opening sizes of 710, 500, 355, 250, 150, 106 and 53 microns were used. SVD was calculated using a computer program based on data on particle size distribution and the total percentage of sifting.

Particle size analysis was carried out using the tablet dispersion of Example 9 according to the following method.

The particle size distribution was determined using a Malvern 2600 particle analyzer as follows. The device was set up to analyze particles in a liquid using a magnetic stirrer. For this purpose, a lens with a focal length of 300 mm was used.

1. Disperse the tablet in 100 ml of deionized water.

2. Stir the solution for approximately 2 hours.

3. Filter or centrifuge the solution to obtain a liquid that should be saturated with all the components that make up the tablet.

4. Disperse the second tablet in 50 ml of unsaturated liquid, allowing to stand for 3 minutes to ensure complete dispersion. Mix vigorously and sample the dispersion for 5 minutes by introducing a sufficient amount into the Malvern PIL cell containing liquid to produce an observed value of 0.15-0.30. Analyze the sample.

Claim

1. A water-dispersible tablet formed from granules containing a pharmaceutically active compound, a pharmaceutically acceptable swelling clay and targeted additives, characterized in that, as a pharmaceutically active compound, it contains a compound selected from the group consisting of an analgesic derivative of propionic acid, a tranquilizing benzodiazepine, antiviral nucleoside derivative, naphthoquinone antiprotozoan compound, allopurinol, oxopurinol, anticonvulsant 1,2,4-triazine derivative, trimethoprim, trimethoprim in combination with sulfomethoxazole, pharmaceutically acceptable swelling clay is a dispersing agent and is contained within the granules of the tablet, which is capable of dispersing in water in over a 3-minute period of time with the formation of a dispersion consisting of particles with a size of less than 710 microns, and the tablet contains the specified components in the following ratio, wt.%:

• Specified pharmaceutically active compound - 5 - 95
• Pharmaceutically acceptable swelling clay - 0.25 - 60.0
• Targeted Supplements - Rest

2. A tablet according to claim 1, characterized in that it is coated with a film membrane and is capable of dispersing in water to form a dispersion consisting of particles with a size of less than 710 microns.

3. A tablet according to claim 1, characterized in that it is capable of dispersing in water over a 2-minute period of time.

4. A tablet according to any one of claims 1 to 3, characterized in that it is capable of dispersing in water to form a dispersion consisting of particles, more than 50% of which have a size of less than 310 microns.

5. A tablet according to claim 4, characterized in that it is capable of dispersing in water to form a dispersion consisting of particles, more than 70% of which have a size of less than 310 microns, and more than 50% of which have a size of less than 200 microns.

6. A tablet according to any one of claims 1 to 5, characterized in that, as a pharmaceutically active compound, it contains a compound selected from the group consisting of acyclovir, lamotrigine, diazepam, paracetamol, 1-(β-D-arabinofuranosyl) 5-propyl -1-ynyluracil, 2-3-hydroxy-1,4-naphthoquinone, allopurinol, 3"-azido-3"-deoxythymidine, 5-propyl-1-ynyl-1-(5-trimethylacetyl-β-D-arabinofuranosyl )-uracil, 2- -ethyl valinate, 2",3"-dideoxy-5-ethynyl-3"-fluorouridine, 5-chloro-1-(2,3-dideoxy-3-fluoro-β-erythropentofuranosyl)-uracil, penciclovir, famciclovir, E-5-(2-bromovinyl)-1-β-arabinofuranosyluracil, dextromethorphan, pseudophedrine, arivastine, triprolidine, guaifenesin, dihydrocodeine, codeine phosphate and ascorbic acid.

7. A tablet according to any one of claims 1 to 6, characterized in that it contains attapulgite as a pharmaceutically acceptable swelling clay.

8. A tablet according to any one of claims 1 to 6, characterized in that it contains clay from the montmorillonite group as a pharmaceutically acceptable swelling clay.

9. A tablet according to claim 8, characterized in that it contains smectite or bentonite or “Veegum F” clay as clay from the montmorillonite group.

10. A tablet according to any one of claims 1 to 9, characterized in that it contains pharmaceutically acceptable swelling clay in an amount of 0.25 to 40 wt.%.

11. A tablet according to claim 10, characterized in that it contains a pharmaceutically acceptable swelling clay in an amount of 1 to 10 wt.%.

12. A tablet according to any one of claims 1 to 11, characterized in that it contains a pharmaceutically active compound in an amount of 5 to 90 wt.%.

13. A tablet according to any one of claims 1 to 12, characterized in that it contains 5 to 90 wt.% of a pharmaceutically active compound, 0.25 to 60 wt.% of a pharmaceutically acceptable swelling clay, 0.1 to 5 wt.% of a lubricant substances and targeted additives - the rest, with the lubricant contained outside the granules.

14. A tablet according to claim 13, characterized in that it contains, as target additives, no more than 25 wt.% of a binder, no more than 20 wt.% of a disintegrant, no more than 95 wt.% of a water-soluble filler, no more than 95% of an insoluble filler filler in water, no more than 5 wt.% surfactant, no more than 10 wt.% sweeteners, as well as dyes and flavoring additives.

15. A tablet according to any one of claims 1 to 14, characterized in that it contains acyclovir as a pharmaceutically active compound.

16. A tablet according to claim 15, characterized in that it contains acyclovir in an amount of 50 - 90 wt.%, and a pharmaceutically acceptable swelling clay in an amount of 0.5 - 40 wt.%.

17. A tablet according to claim 16, characterized in that it contains 200 - 800 mg of acyclovir.

18. A tablet according to claim 16, characterized in that it contains 70 - 90 wt.% acyclovir, 0.5 - 30 wt.% bentonite clay or Veegum F clay, 0.25 - 5 wt.% polyvinylpyrrolidone or starch , swelling in cold water, 5 - 25 wt. % microcrystalline cellulose or low-substituted hydroxypropylcellulose, 0.25 - 2 wt.% magnesium stearate.

19. Tablet according to claim 18, characterized in that it additionally contains no more than 8 wt.% sodium starch glycolate.

20. A tablet according to claim 18 or 19, characterized in that it is coated with a polymer membrane from the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.1 - 2 wt.%, or a membrane of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.5 wt.%.

21. A tablet according to claim 18, characterized in that it contains 75 - 85 wt.% acyclovir, 0.5 - 10 wt.% bentonite clay or Veegum F clay, 0.5 - 2 wt.% polyvinylpyrrolidone or starch , swelling in cold water, 5 - 15 wt. % microcrystalline cellulose or low-substituted hydroxypropylcellulose, 0.25 - 2 wt.% magnesium stearate.

22. The tablet according to claim 21, characterized in that it additionally contains no more than 5 wt.% sodium starch glycolate.

23. A tablet according to claim 21 or 22, characterized in that it is coated with a film membrane of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25 - 1 wt.% or a membrane of polyethylene glycol 8000, taken in an amount of 0.1 - 0.2 wt.%.

24. A tablet according to any one of claims 1 - 9, characterized in that it contains acyclovir as a pharmaceutically active compound in an amount of 750 - 850 mg with a total tablet weight of 1000 - 1200 mg.

25. A tablet according to claim 24, characterized in that it contains pharmaceutically acceptable swelling clay in an amount of 40 - 120 mg.

26. A tablet according to any one of claims 1 to 14, characterized in that it contains lamotrigine as a pharmaceutically active compound.

27. A tablet according to claim 26, characterized in that it contains lamotrigine in an amount of 2 - 90 wt.%, and a pharmaceutically acceptable swelling clay in an amount of 0.25 - 40 wt.%.

28. Tablet according to claim 27, characterized in that it contains 25 - 200 mg of lamotrigine.

29. A tablet according to claim 27, characterized in that it contains 30 - 50 wt.% lamotrigine, 0.25 - 30 wt.% bentonite clay or Veegum F clay, 26 - 46 wt.% calcium carbonate, 5 - 30 wt.% microcrystalline cellulose or low-substituted hydroxypropylcellulose, 1 - 8 wt.% polyvinylpyrrolidone or cold water swelling starch, 0.25 - 2 wt.% magnesium stearate.

30. A tablet according to claim 29, characterized in that it additionally contains no more than 8 wt.% sodium starch glycolate.

31. A tablet according to claim 29 or 30, characterized in that it is coated with a film membrane of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25 - 1 wt.%, or a membrane of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.5 wt.%.

32. A tablet according to claim 29, characterized in that it contains 35 - 45 wt.% lamotrigine, 0.25 - 10 wt.% bentonite clay or Veegum F clay, 31 - 41 wt.% calcium carbonate, 5 - 15 wt.% microcrystalline cellulose or low-substituted hydroxypropylcellulose, 2 - 5 wt.% polyvinylpyrrolidone or cold water swelling starch, 0.25 - 1 wt.% magnesium stearate.

33. The tablet according to claim 32, characterized in that it additionally contains no more than 5 wt.% sodium starch glycolate.

34. A tablet according to claim 32 or 33, characterized in that it is coated with a film membrane of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25 - 1 wt.%, or a membrane of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.2 wt.%.

35. A tablet according to claim 27, characterized in that it contains 5 to 50 mg of lamotrigine.

36. A tablet according to claim 27, characterized in that it contains 3 - 13 wt.% lamotrigine, 50 - 60 wt.% lactose or calcium carbonate, 20 - 35 wt.% microcrystalline cellulose or low-substituted hydroxypropylcellulose, 0.25 - 30 wt.% bentonite clay or clay "Veegum F", 1 - 8 wt.% polyvinylpyrrolidone or cold water swelling starch, 0.25 - 2 wt.% magnesium stearate.

37. The tablet according to claim 36, characterized in that it additionally contains no more than 8 wt.% sodium starch glycolate, no more than 0.5 wt.% sodium docusate and no more than 3 wt.% sodium saccharin.

38. A tablet according to claim 36 or 37, characterized in that it is coated with a polymer film membrane from the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.1 - 2 wt.%, or a membrane of polyethylene glycol 8000, taken in an amount of 0 .1 - 0.5 wt.%.

39. A tablet according to claim 36, characterized in that it contains 5 - 11 wt.% lamotrigine, 53 - 59 wt.% lactose or calcium carbonate, 24 - 30 wt.% microcrystalline cellulose or low-substituted hydroxypropylcellulose, 0.25 - 10 wt.% bentonite clay or clay "Veegum F", 2 - 5 wt.% polyvinylpyrrolidone or cold water swelling starch, 0.25 - 1 wt.% magnesium stearate.

40. A tablet according to claim 39, characterized in that it additionally contains no more than 5 wt.% sodium starch glycolate, 0.15 - 0.5 wt.% sodium docusate, 0.5 - 2 wt.% sodium saccharin.

41. A tablet according to claim 39 or 40, characterized in that it is coated with a polymer film membrane from the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25 - 1 wt.%, or a membrane of polyethylene glycol 8000, taken in an amount of 0 .1 - 0.2 wt.%.

42. A method for producing a water-dispersible tablet, comprising mixing in finely divided form a pharmaceutically active compound with target additives and a pharmaceutically acceptable swelling clay, adding a pharmaceutically acceptable liquid in an amount sufficient to moisten the dry mixture, granulating the resulting wet mixture to obtain granules, drying the granules, mixing these granules with target additives and compressing the granules to form a tablet, characterized in that the components according to claim 1 are used, a pharmaceutically acceptable swelling clay is contained within the granules of the resulting tablet, which is capable of dispersing in water over a 3-minute period of time to form a dispersion, consisting of particles smaller than 710 microns.

43. Granules for water-dispersible tablets containing a pharmaceutically active compound, a pharmaceutically acceptable swelling clay and targeted additives, characterized in that they contain components according to any one of paragraphs. 1 - 41, and a pharmaceutically acceptable swelling clay is contained within the granules.

44. Use of a pharmaceutically acceptable swelling clay as a dispersing agent in a water-dispersible tablet according to any one of claims 1 to 41.

Inventor's name: Krystyna Elzbieta Fielden
Patent owner's name: Dze Wellcome Foundation Limited (GB)
Patent start date: 1992.01.29

Registration number: LP 001805-160414
Trade name of the drug: Prestarium® A
International nonproprietary name: perindopril arginine (modified international nonproprietary name)
Dosage form: oral dispersible tablets
Compound:
Tablet 2.5 mg
Active substance: perindopril arginine 2.5 mg (1.698 mg in terms of perindopril).
Excipients:
Acesulfame potassium 0.1 mg, aspartame 0.1 mg, magnesium stearate 0.2 mg, colloidal silicon dioxide anhydrous 0.2 mg, dry mixture of lactose and starch (lactose monohydrate 85%, corn starch 15%) 36.9 mg.
5 mg tablet
Active substance: perindopril arginine 5 mg (3.395 mg in terms of perindopril).
Excipients:
Acesulfame potassium 0.2 mg, aspartame 0.2 mg, magnesium stearate 0.4 mg, colloidal silicon dioxide anhydrous 0.4 mg, dry mixture of lactose and starch (lactose monohydrate 85%, corn starch 15%) 73.8 mg.
10 mg tablet
Active substance: perindopril arginine 10 mg (6.790 mg in terms of perindopril).
Excipients:
Acesulfame potassium 0.4 mg, aspartame 0.4 mg, magnesium stearate 0.8 mg, colloidal silicon dioxide anhydrous 0.8 mg, dry mixture of lactose and starch (lactose monohydrate 85%, corn starch 15%) 147.6 mg.
Description
Round, biconvex, white tablets.
Pharmacotherapeutic group: angiotensin-converting enzyme (ACE) inhibitor
ATX code: S09AA04

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
Mechanism of action
Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II. ACE, or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I into the vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. As a result, perindopril reduces the secretion of aldosterone.
Since angiotensin-converting enzyme inactivates bradykinin, ACE suppression is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive action of ACE inhibitors, as well as the mechanism of development
some side effects of drugs in this class (for example, cough).
Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites do not have an ACE inhibitory effect in vitro.
Clinical efficacy and safety

Perindopril is effective in the treatment of arterial hypertension of any severity. With the use of the drug, there is a decrease in both systolic and diastolic blood pressure (BP) in the patient’s “lying” and “standing” positions.
Perindopril reduces total peripheral vascular resistance (TPVR), which leads to a decrease in blood pressure, while peripheral blood flow accelerates without changing heart rate (HR).
As a rule, perindopril leads to an increase in renal blood flow, while the glomerular filtration rate does not change.
The antihypertensive effect of the drug reaches a maximum 4-6 hours after a single oral dose and persists for 24 hours. 24 hours after oral administration, pronounced (about 80%) residual ACE inhibition is observed.
A decrease in blood pressure is achieved quite quickly. In patients with a positive response to treatment, normalization of blood pressure occurs within a month and is maintained without the development of tachycardia.
Termination of treatment is not accompanied by the development of withdrawal syndrome.
Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.
The simultaneous administration of thiazide diuretics increases the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia while taking diuretics.

Perindopril normalizes heart function by reducing preload and afterload.
In patients with chronic heart failure treated with perindopril, the following was found:
- decrease in filling pressure in the left and right ventricles of the heart;
- decrease in total peripheral vascular resistance;
- increased cardiac output and increased cardiac index.
A study of the drug compared with placebo showed that changes in blood pressure after the first dose of Prestarium® A 2.5 mg in patients with chronic heart failure (II - III functional class according to the NYHA classification) were not statistically significantly different from the changes in blood pressure observed after taking placebo.

Results of the PROGRESS study, which assessed the effect of active therapy with perindopril (monotherapy or in combination with indapamide) for 4 years on the risk of recurrent stroke in patients with a history of cerebrovascular disease. After an introductory period of perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg) once daily for two weeks and then 4 mg (equivalent to perindopril arginine 5 mg) once daily for the next two weeks, 6105 patients were randomized into two groups: placebo (n=3054) and perindopril tert-butylamine 4 mg (corresponding to 5 mg perindopril arginine) (monotherapy) or in combination with indapamide (n=3051). Indapamide was additionally prescribed to patients who did not have direct indications or contraindications for the use of diuretics. This therapy was prescribed in addition to standard therapy for stroke and/or arterial hypertension or other pathological conditions. All randomized patients had a history of cerebrovascular disease (stroke or transient ischemic attack) within the past 5 years. Blood pressure was not an inclusion criterion: 2916 patients had arterial hypertension and 3189 had normal blood pressure. After 3.9 years of therapy, blood pressure (systolic/diastolic) decreased by an average of 9.0/4.0 mm Hg. It also showed a significant reduction in the risk of recurrent stroke (both ischemic and hemorrhagic) of the order of 28% (95% CI (17; 38), p< 0,0001) по сравнению с плацебо (10,1 % и 13,8 %).
Additionally, significant risk reductions have been shown:
- fatal or disabling strokes;
- major cardiovascular complications, including myocardial infarction, incl. with fatal outcome;
- dementia associated with stroke;
- serious deterioration of cognitive functions.
This was noted both in patients with arterial hypertension and in those with normal blood pressure, regardless of age, gender, presence or absence of diabetes mellitus and type of stroke.

It has been shown that when taking perindopril tertbutylamine at a dose of 8 mg/day (equivalent to 10 mg perindopril arginine) in patients with stable coronary artery disease, there is a significant reduction in the absolute risk of complications provided for by the main criterion of effectiveness (mortality from cardiovascular diseases, incidence of non-fatal myocardial infarction and/or cardiac arrest followed by successful resuscitation) by 1.9%. In patients who had previously had a myocardial infarction or coronary revascularization procedure, the absolute risk reduction was 2.2% compared with the placebo group.

Pharmacokinetics
Suction
When taken orally, perindopril is rapidly absorbed from the gastrointestinal tract, the maximum concentration (Cmax) in the blood plasma is reached after 1 hour. The half-life (T1/2) of perindopril from the blood plasma is 1 hour.
Perindopril has no pharmacological activity. Approximately 27% of the total amount of absorbed perindopril enters the bloodstream in the form of the active metabolite perindoprilate. In addition to perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. Cmax of perindoprilate in blood plasma is achieved 3-4 hours after oral administration.
Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, the drug should be taken orally once a day, in the morning, before meals.
Distribution
The volume of distribution of free perindoprilate is approximately 0.2 l/kg. The association of perindoprilate with plasma proteins, mainly with ACE, is insignificant and dose-dependent.
Removal
Perindoprilat is excreted by the kidneys. T1/2 of the free fraction is 3-5 hours. “Effective” T1/2 is approximately 17 hours, the equilibrium state is achieved within 4 days.
Special patient groups
The elimination of perindoprilate is slowed in old age, as well as in patients with heart and renal failure.
The dialysis clearance of perindoprilate is 70 ml/min.
In patients with liver cirrhosis, the hepatic clearance of perindopril is reduced by 2 times. However, the amount of perindoprilate formed does not decrease, and no dose adjustment of the drug is required (see sections “Dosage and Administration” and “Special Instructions”).

INDICATIONS FOR USE

Arterial hypertension;
- chronic heart failure;
- prevention of recurrent stroke (combination therapy with indapamide) in patients who have suffered a stroke or transient ischemic cerebrovascular accident;
- stable coronary artery disease: reducing the risk of cardiovascular complications in patients with stable coronary artery disease.

CONTRAINDICATIONS

Hypersensitivity to the active substance, other ACE inhibitors and excipients (see section “Composition”) included in the drug;
- history of angioedema (Quincke's edema) associated with taking an ACE inhibitor;
- hereditary/idiopathic angioedema;
- pregnancy();
- breastfeeding period ( see section “Use during pregnancy and breastfeeding”);
- simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (glomerular filtration rate (GFR)< 60 мл/мин/1,73м 2) (см. разделы «Особые указания» и «Взаимодействие с другими лекарственными препаратами»);
- lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;
- age under 18 years (efficacy and safety have not been established).

CAREFULLY

(see also sections “Special instructions” and “Interaction with other drugs”)
Bilateral renal artery stenosis or the presence of only one functioning kidney, renal failure, systemic connective tissue diseases (systemic lupus erythematosus, scleroderma, etc.), therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), reduced circulating blood volume (taking diuretics , salt-free diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure functional class IV according to the NYHA classification, simultaneous use of potassium-sparing diuretics, potassium supplements, potassium-containing substitutes for table salt and lithium, hyperkalemia, surgery/ general anesthesia, hemodialysis using high-flow membranes, desensitization therapy, low-density lipoprotein (LDL) apheresis, condition after kidney transplantation, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, use in black patients.

Use during pregnancy and breastfeeding

Pregnancy
Prestarium® A is contraindicated for use during pregnancy (see section “Contraindications”).
Prestarium® A should not be used in the first trimester of pregnancy. If you are planning pregnancy or if it occurs while using the drug Prestarium® A, you should immediately stop taking the drug and, if necessary, prescribe other antihypertensive therapy with a proven safety profile for use during pregnancy.
It is known that the effect of ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to disruption of its development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).
If the patient received ACE inhibitors during the second or third trimester of pregnancy, it is recommended to conduct an ultrasound examination of the newborn to assess the condition of the skull bones and renal function.
Breastfeeding period
It is not known whether perindopril passes into breast milk. Therefore, the use of Prestarium® A during breastfeeding is not recommended.
If the use of the drug is necessary during lactation, then breastfeeding should be discontinued.
Fertility
Preclinical studies have shown no effect of perindopril on reproductive function in rats of both sexes.

METHOD OF APPLICATION AND DOSES

Orally, 1 tablet 1 time per day, preferably in the morning, before meals.
The tablet should be placed on the tongue and after it disintegrates on the surface of the tongue, swallow it with saliva.
When choosing a dose, you should take into account the characteristics of the clinical situation (see section “Special Instructions”) and the degree of reduction in blood pressure during therapy.

Prestarium® A can be used both in monotherapy and as part of combination therapy.
The recommended starting dose is 5 mg once daily.
In patients with pronounced activity of the renin-angiotensin-aldosterone system (RAAS) (especially with renovascular hypertension, hypovolemia and/or decreased plasma electrolytes, decompensated chronic heart failure or severe arterial hypertension), a pronounced decrease in blood pressure may develop after taking the first dose of the drug . At the beginning of therapy, such patients should be under close medical supervision. The recommended starting dose for such patients is 2.5 mg once daily.
If necessary, a month after the start of therapy, you can increase the dose of the drug to 10 mg 1 time per day.
At the beginning of therapy with Prestarium® A, symptomatic arterial hypotension may occur. In patients simultaneously receiving diuretics, the risk of developing arterial hypotension is higher due to possible hypovolemia and a decrease in plasma electrolytes. Caution should be exercised when using Prestarium® A in this group of patients.
It is recommended, if possible, to stop taking diuretics 2-3 days before the intended start of therapy with Prestarium® A (see section “Special Instructions”).
If it is impossible to cancel diuretics, the initial dose of Prestarium® A should be 2.5 mg. In this case, it is necessary to monitor kidney function and potassium levels in the blood serum. In the future, if necessary, the dose of the drug can be increased. If necessary, diuretics can be resumed.
In elderly patients, treatment should begin with a dose of 2.5 mg per day. If necessary, a month after the start of therapy, the dose can be increased to 5 mg per day, and then to a maximum dose of 10 mg per day, taking into account the state of renal function (see Table 1).
The maximum daily dose is 10 mg.

Treatment of patients with chronic heart failure with Prestarium® A in combination with non-potassium-sparing diuretics and/or digoxin and/or beta-blockers is recommended to begin under close medical supervision, prescribing the drug at an initial dose of 2.5 mg once a day, in the morning. After two weeks of treatment, the dose of the drug can be increased to 5 mg once a day, provided that the dose of 2.5 mg is well tolerated and the response to therapy is satisfactory.
In patients at high risk of developing symptomatic arterial hypotension, for example, with reduced electrolyte levels with or without hyponatremia, hypovolemia, or taking diuretics, these conditions should, if possible, be corrected before starting Prestarium® A. Indicators such as blood pressure, renal function and potassium levels in the blood plasma should be monitored both before and during therapy.

In patients with a history of cerebrovascular disease, therapy with Prestarium® A should be started with a dose of 2.5 mg during the first two weeks, then increasing the dose to 5 mg over the next two weeks before using indapamide.
Therapy should begin at any time (from two weeks to several years) after a stroke.

In patients with stable coronary artery disease, therapy with Prestarium® A should be started with a dose of 5 mg once a day.
After 2 weeks, if the drug is well tolerated and taking into account the state of renal function, the dose can be increased to 10 mg 1 time per day.
Elderly patients should begin therapy with a dose of 2.5 mg once daily for one week, then 5 mg once daily for the next week. Then, taking into account the state of renal function, the dose can be increased to 10 mg 1 time per day (see Table 1). The dose of the drug can be increased only if it is well tolerated at the previously recommended dose.
Special patient groups

In patients with renal failure, the dose of the drug should be adjusted taking into account creatinine clearance (CC).

Table 1. Dosage of the drug Prestarium® A for renal failure

* dialysis clearance of perindoprilate - 70 ml/min. The drug should be taken after the dialysis procedure.

Patients with impaired liver function do not require dose adjustment (see sections “Pharmacokinetics” and “Special instructions”).

Prestarium® A should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of the drug in patients in this age group.

SIDE EFFECT

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.
The most common adverse events reported in clinical studies and observed with perindopril are: dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, excessive decrease in blood pressure, cough, shortness of breath, abdominal pain, constipation, diarrhea, taste disturbance, dyspepsia, nausea, vomiting, itching, skin rash, muscle spasms and asthenia.
The frequency of adverse reactions that were noted during clinical trials and/or post-registration use of perindopril is given in the following gradation: very often (≥1/10); often (≥1/100,<1/10); нечасто (≥1/1000, <1/100); редко (≥1/10000, <1/1000); очень редко (<1/10000); неуточненной частоты (частота не может быть подсчитана по доступным данным). Классификация показателей частоты рекомендована Всемирной организацией здравоохранения (ВОЗ).
From the blood and lymphatic system
Infrequently*: eosinophilia.
Very rarely: decrease in hemoglobin and hematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis, pancytopenia, hemolytic anemia in patients with congenital deficiency of glucose-6-phosphate dehydrogenase (see section "Special instructions").
Metabolic disorders
Infrequently*: hypoglycemia (see sections “Special instructions” and “Interaction with other drugs”), hyperkalemia, reversible after discontinuation of the drug (see section “Special instructions”), hyponatremia.
From the central nervous system
Often: paresthesia, headache, dizziness, vertigo.
Infrequently: sleep disturbances, mood lability, drowsiness*, fainting*.
Very rarely: confusion.
From the side of the organ of vision
Often: visual impairment.
From the side of the hearing organ
Often: noise in ears.
From the cardiovascular system
Often: excessive decrease in blood pressure and associated symptoms.
Infrequently*: vasculitis, tachycardia, palpitations.
Very rarely: cardiac arrhythmias, angina pectoris, myocardial infarction and stroke, possibly due to an excessive decrease in blood pressure in high-risk patients (see section "Special Instructions").
From the respiratory system
Often: cough, shortness of breath.
Infrequently: bronchospasm.
Very rarely: eosinophilic pneumonia, rhinitis.
From the digestive system
Often: constipation, nausea, vomiting, abdominal pain, taste disturbance, dyspepsia, diarrhea.
Infrequently: dryness of the oral mucosa.
Very rarely: pancreatitis.
From the liver and biliary tract
Very rarely: hepatitis (cholestatic or cytolytic) (see section “Special instructions”).
From the skin and subcutaneous fat
Often: skin itching, rash.
Infrequently: angioedema of the face, lips, upper and lower extremities, mucous membranes, tongue, vocal folds and/or larynx; urticaria (see section “Special instructions”).
Very rarely: erythema multiforme.
Infrequently*: photosensitivity, pemphigus, increased sweating.
From the musculoskeletal system and connective tissue
Often: muscle spasms.
Infrequently*: arthralgia, myalgia.
From the kidneys and urinary tract
Infrequently: renal failure.
Very rarely: acute renal failure.
From the reproductive system
Infrequently: erectile disfunction.
Common disorders and symptoms
Often: asthenia.
Infrequently: chest pain*, peripheral edema*, weakness*, fever*, falls*.
Laboratory indicators
Rarely: increased activity of “liver” transaminases and bilirubin in the blood serum.
Infrequently*: increased concentrations of urea and creatinine in the blood plasma.
* The frequency of adverse reactions identified by spontaneous reports was assessed based on the results of clinical trials.
Adverse events noted in clinical studies
The EUROPA study recorded only serious adverse events. Serious adverse events were reported in 16 (0.3%) patients in the perindopril group and 12 (0.2%) patients in the placebo group. In the perindopril group, a marked decrease in blood pressure was observed in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. The rate of drug discontinuation due to cough, severe decrease in blood pressure, or other cases of intolerance was higher in the perindopril group compared with the placebo group.

OVERDOSE

Data on drug overdose are limited.
Symptoms: marked decrease in blood pressure, shock, water-electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.
Treatment
Emergency measures are limited to removing the drug from the body: gastric lavage and/or taking activated charcoal, followed by restoration of water and electrolyte balance.
If there is a significant decrease in blood pressure, the patient should be transferred to the “lying” position on his back with his legs elevated. If necessary, 0.9% sodium chloride solution should be administered intravenously. If necessary, a solution of catecholamines can be administered intravenously. Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis. If treatment-resistant bradycardia develops, it may be necessary to install an artificial pacemaker. It is necessary to constantly monitor indicators of basic vital functions of the body, the concentration of creatinine and electrolytes in the blood serum.

INTERACTIONS WITH OTHER MEDICINES

Certain drugs or drugs from other pharmacological classes may increase the risk of developing hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists (ARA II), non-steroidal anti-inflammatory drugs (NSAIDs), heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Combining these drugs increases the risk of hyperkalemia.
(see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or impaired renal function (GFR less than 60 ml/min), the risk of hyperkalemia, deterioration of renal function and increased incidence of cardiovascular morbidity and mortality increases.
(see section "Special instructions")
Aliskiren
In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, deterioration of renal function, and increased incidence of cardiovascular morbidity and mortality.

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an ARB II is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure). ) compared to the use of only one drug that affects the RAAS. Dual blockade (for example, when combining an ACE inhibitor with an ARB II) should be limited to selected cases with careful monitoring of renal function, potassium levels and blood pressure.
Estramustine
Concomitant use may result in an increased risk of adverse effects such as angioedema.

Hyperkalemia(possibly fatal), especially if renal function is impaired (additional effects associated with hyperkalemia).
The combination of perindopril with the above-mentioned drugs is not recommended (see section "Special instructions"). If, however, concomitant use is indicated, they should be used with caution and regular monitoring of serum potassium levels.
Features of the use of spironolactone in heart failure are described below.
Lithium preparations
With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and associated toxic effects may be observed. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, the concentration of lithium in the blood plasma should be regularly monitored (see section “Special Instructions”).
Concomitant use requiring extreme caution
Hypoglycemic agents (insulin, hypoglycemic agents for oral administration)
The use of ACE inhibitors can enhance the hypoglycemic effect of insulin and oral hypoglycemic agents up to the development of hypoglycemia. As a rule, this is observed in the first weeks of simultaneous therapy and in patients with impaired renal function.
Baclofen
Enhances the antihypertensive effect of ACE inhibitors. Blood pressure levels and, if necessary, dosage of antihypertensive drugs should be carefully monitored.

In patients receiving diuretics, especially those that remove fluid and/or salts, an excessive decrease in blood pressure may be observed at the beginning of perindopril therapy, the risk of which can be reduced by discontinuing the diuretic, replacing fluid or salt loss before starting perindopril therapy, as well as prescribing perindopril at low levels. dose with further gradual increase.
For arterial hypertension In patients receiving diuretics, especially those that remove fluid and/or salts, the diuretics should either be discontinued before starting the ACE inhibitor (at the same time, a potassium-sparing diuretic may be reintroduced later), or the ACE inhibitor should be prescribed at a low dose and then gradually tapered increase.
When using diuretics in case of chronic heart failure An ACE inhibitor should be prescribed at a low dose, possibly after reducing the dose of a concomitantly used potassium-sparing diuretic. In all cases, renal function (creatinine concentration) should be monitored in the first weeks of using ACE inhibitors.
Potassium-sparing diuretics (eplerenone, spironolactone)
The use of eplerenone or spironolactone in doses from 32.5 mg to 50 mg per day and low doses of ACE inhibitors:
When treating heart failure of functional class II - IV according to the NYHA classification with left ventricular ejection fraction. Before using this combination of drugs, you must ensure that there is no hyperkalemia and renal dysfunction.
It is recommended to regularly monitor the concentration of creatinine and potassium in the blood: weekly in the first month of treatment and monthly thereafter.
NSAIDs, including high doses of acetylsalicylic acid (more than 3 g/day)
The simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should receive adequate fluids, and close monitoring of renal function is recommended, both initially and during treatment.
Concomitant use which requires some caution
Antihypertensive drugs and vasodilators
The antihypertensive effect of perindopril may be enhanced when used simultaneously with other antihypertensive and vasodilating agents, including short- and long-acting nitrates.
Gliptins (linagliptin, saxagliptin, sitagliptin, vitagliptin)
Concomitant use with ACE inhibitors may increase the risk of angioedema due to inhibition of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.
Tricyclic antidepressants, antipsychotics (neuroleptics) and general anesthetics
Concomitant use with ACE inhibitors may lead to increased antihypertensive effects (see section "Special Instructions").
Sympathomimetics
May weaken the antihypertensive effect of ACE inhibitors.
Gold preparations
When using ACE inhibitors, including perindopril, in patients receiving intravenous gold (sodium aurothiomalate), a symptom complex was described, including facial flushing, nausea, vomiting, and arterial hypotension.

SPECIAL INSTRUCTIONS

IHD: reducing the risk of cardiovascular complications in patients who have previously had myocardial infarction and/or coronary revascularization
If unstable angina develops during the first month of therapy with Prestarium® A, the benefits and risks should be assessed before continuing therapy.
Arterial hypotension
ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension rarely develops in patients with uncomplicated arterial hypertension. The risk of an excessive decrease in blood pressure is increased in patients with reduced blood volume, which can be observed during diuretic therapy, while following a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity (see sections “Interaction” with other drugs" and "Side effects"). In patients at increased risk of developing symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with Prestarium® A.
A similar approach is used in patients with coronary artery disease and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.
If arterial hypotension develops, the patient should be transferred to the supine position with legs elevated. If necessary, the volume of circulating blood should be replenished with intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further taking the drug. After restoration of blood volume and blood pressure, treatment can be continued.
In some patients with chronic heart failure (CHF) and normal or low blood pressure, Prestarium® A may cause an additional decrease in blood pressure. This effect is predictable and does not usually require discontinuation of therapy. If symptoms of a pronounced decrease in blood pressure appear, the dose of the drug should be reduced or discontinued.
Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy
Prestarium® A, like other ACE inhibitors, should be administered with caution to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as to patients with mitral stenosis.
Renal dysfunction
For patients with renal failure (creatinine clearance less than 60 ml/min), the initial dose of Prestarium® A is selected depending on the clearance value (see section “Method of administration and dosage”) and then depending on the therapeutic effect. For such patients, regular monitoring of serum creatinine and potassium concentrations is necessary (see section “Side Effects”).
Hypotension, which sometimes develops when starting ACE inhibitors in patients with symptomatic CHF, can lead to deterioration of renal function. Acute renal failure may develop, usually reversible. In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney (especially in the presence of renal failure), during therapy with ACE inhibitors, there may be an increase in the concentration of urea and creatinine in the blood serum, which usually resolves when therapy is discontinued. The additional presence of renovascular hypertension causes an increased risk of severe hypotension and renal failure in such patients.
Treatment of such patients begins under close medical supervision using low doses of the drug and further adequate selection of doses. Treatment with diuretics should be temporarily discontinued and plasma potassium and creatinine levels should be regularly monitored during the first few weeks of therapy.
In some patients with arterial hypertension without indication of pre-existing renal vascular disease, serum urea and creatinine concentrations may increase, especially with simultaneous use of diuretics. These changes are usually mild and reversible. The likelihood of developing these disorders is higher in patients with a history of renal failure. In such cases, it may be necessary to discontinue or reduce the dose of Prestarium® A and/or the diuretic.
Hemodialysis
In patients undergoing hemodialysis using high-flux membranes (for example, AN69®), cases of anaphylactic reactions have been reported during therapy with ACE inhibitors. Prescription of ACE inhibitors should be avoided when using this type of membrane.
Kidney transplant
There are no data on the use of Prestarium® A in patients after kidney transplantation.
Hypersensitivity/angioedema
When taking ACE inhibitors, including perindopril, in rare cases and during any period of therapy, the development of angioedema of the face, upper and lower extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may be observed (see section “Side effects”). action"). If symptoms appear, the drug should be stopped immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, emergency treatment is required, including subcutaneous administration of epinephrine (adrenaline) and/or maintaining the airway. The patient should be under medical supervision until symptoms disappear completely and permanently.
Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section "Contraindications").
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C1-esterase. The diagnosis was made using abdominal computed tomography, ultrasound, or surgery. Symptoms disappeared after stopping the ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine (see section “Side effects”).
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextrin sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Anaphylactoid reactions during desensitization
There are isolated reports of the development of anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy, such as hymenoptera venom. ACE inhibitors should be used with caution in patients susceptible to allergic reactions undergoing desensitization procedures. The use of ACE inhibitors should be avoided in patients receiving bee venom immunotherapy. However, this reaction can be avoided by temporarily discontinuing the ACE inhibitor before starting the desensitization procedure.
Liver dysfunction
In rare cases, while taking ACE inhibitors, a syndrome of development of cholestatic jaundice with transition to fulminant liver necrosis, sometimes with death, was observed. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of liver enzymes occurs while taking ACE inhibitors, you should stop taking the drug (see section “Side Effects”), the patient should be under appropriate medical supervision.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
While taking ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia and anemia may occur. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Prestarium® A should be used with extreme caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.
Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing Prestarium® A to such patients, it is recommended to periodically monitor the level of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.
Ethnic differences
It should be taken into account that patients of the Negroid race have a higher risk of developing angioedema. Like other ACE inhibitors, Prestarium® A is less effective in lowering blood pressure in black patients.
This effect may be associated with a pronounced predominance of low-renin status in black patients with arterial hypertension.
Cough
During therapy with an ACE inhibitor, a persistent dry cough may occur, which stops after discontinuation of the drug. This should be taken into account when carrying out the differential diagnosis of cough.
Surgery/general anesthesia
The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a significant decrease in blood pressure, especially when using drugs for general anesthesia that have an antihypertensive effect. Taking Prestarium® A should be stopped one day before surgery. If arterial hypotension develops, blood pressure should be maintained by replenishing blood volume. It is necessary to warn the surgeon/anesthesiologist that the patient is taking ACE inhibitors.
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, decreased renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride) , potassium supplements/preparations or potassium-containing table salt substitutes, as well as the use of other drugs that increase potassium levels in the blood (for example, heparin). The use of potassium supplements/preparations, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If simultaneous use of Prestarium® A and the above drugs is necessary, treatment should be carried out with caution against the background of regular monitoring of potassium levels in the blood serum (see section “Interaction with other drugs”).
Patients with diabetes mellitus
When prescribing the drug to patients with diabetes mellitus receiving hypoglycemic agents for oral administration or insulin, during the first month of therapy it is necessary to regularly monitor the concentration of glucose in the blood (see section “Interaction with other drugs”).
Lithium preparations
The simultaneous use of Prestarium® A and lithium preparations is not recommended (see section “Interaction with other drugs”).
Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements
The simultaneous administration of Prestarium® A and potassium-sparing diuretics, as well as potassium preparations, potassium-containing table salt substitutes and food additives is not recommended (see section “Interaction with other drugs”).
Double blockade of the RAAS
Cases of hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal failure) have been reported in susceptible patients, especially when used concomitantly with drugs that affect this system. Therefore, double blockade of the RAAS by combining an ACE inhibitor with an ARA II or aliskiren is not recommended.
Combination with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR

Impact on the ability to drive vehicles and perform work that requires high speed of mental and physical reactions
Prestarium® A should be used with caution in patients driving vehicles and engaged in activities that require increased concentration and quick reaction, due to the risk of developing arterial hypotension and dizziness.