Racialus

Racial is an inhibitor of renin.

[1], [2]

Indications of the racileza

Used to reduce blood pressure in the development of hypertension.

Release form

Release in tablets; on the blister for 7 pieces. Inside a separate package - 2 or 4 blister plates. Also, 14 tablets can be produced on the 1st blister; In this case, 1 or 2 such blister plates are inserted into the packet.

Racialus Nest

Racial is a drug that affects the RAS. A drug that combines with hydrochlorothiazide.

Used in the elimination of primary hypertension in individuals with insufficient control of blood pressure (when monotherapy with aliskiren or hydrochlorothiazide), or in people with adequate control of blood pressure (when using hydrochlorothiazide with aliskiren, which are taken in combination - in doses similar to those , which are observed in combined drugs).

Pharmacodynamics

Aliskiren is an active non-peptide inhibitor of human renin (a direct, selective substance with potent action).

By depressing the enzyme renin, the active substance aliskiren inhibits the RAA system immediately at the time of its activation. This is due to the blocking of the process of conversion of the angiotensinogen element into angiotensin I, and together with this the decrease in the angiotensin I indices, and also II.

Other drugs that depress the function of RAAS (such as ACE inhibitors, as well as drugs blocking the conductors of angiotensin II), cause a compensatory increase in the activity of plasma renin. Aliskiren, on the contrary, lowers the activity of this enzyme in people with elevated blood pressure (approximately 50-80%). A similar effect was observed in the case of combined use of aliskiren and other antihypertensive drugs. The medicinal value of such a difference in the effect on the activity of plasma renin has not yet been determined.

Pharmacokinetics

After using the drug, the absorption of aliskiren takes place, reaching a peak level after 1-3 hours. The bioavailability of a substance is approximately 2-3%. It is necessary to take into account that excessively fatty food reduces the peak level by 85%, and the AUC - by 70%.

Steady-state indices inside the plasma are observed after 5-7 days after taking the medication once a day. The steady-state values of Rasilez are approximately twice as high as those obtained after taking the initial dosage.

Preclinical testing showed that MDR1 / Mdr1a / 1b (substance P-glycoprotein) is the main system of efflux process used for intestinal absorption, as well as biliary excretion of aliskiren.

After the use of the tablet, the average index of the distribution volume (stationary value) is approximately 135 liters, from which it can be concluded that the active component of the drug is well distributed in the extravascular environment.

The synthesis of the component with the plasma protein is rather moderate (about 47-51%). The concentration indices do not affect it.

The half-life is approximately 40 hours (fluctuations within 34-41 hours). Excretion of aliskiren mostly occurs in unchanged form with feces (78%). About 1.4% of the total dosage of drugs passes the metabolic process (the enzyme CYP3A4 is responsible for it). After ingestion, 0.6% of the dose is detected in the urine. The average indicator of the rate of clearance for intravenous injection is approximately 9 liters per hour.

The exposure indices of aliskiren increase more than proportionally to the increase in the dose taken. With the use of a single dose in the interval 75-600 mg in the case of a double increase in the dose, an increase in the peak level and AUC (respectively in 2.6, and also 2.3 times) was observed.

The non-linearity of the drug for stationary indices can be even more vivid. It was not possible to establish a mechanism that causes deviations in the linearity of the drug. The reason may be the saturation of the vectors in the absorption site or the hepatobiliary path of excretion.

Use of the racileza during pregnancy

Information on the use of substances in pregnant women is absent. When testing animals, Racileus did not have a teratogenic effect. Other drugs that have a direct effect on the function of RAAS, were the cause of the development of serious congenital anomalies, as well as the death of newborns.

Like other drugs that directly affect the work of the RAAS, Racileus should not be used during pregnancy planning or during the first trimester. Also, it is contraindicated for admission to the 2nd and 3rd trimesters. When prescribing any medicine from the above group, it is necessary to warn those who are planning a pregnancy about the possible risk of complications when taking the drug during pregnancy. It is required to cancel the drug if during pregnancy pregnancy was detected.

There is no information about the ingestion of aliskiren into breast milk, as a result of which it is forbidden to take medication during the period of feeding.

Contraindications

The main contraindications are:

• hypersensitivity to the active component of the drug or any of its additional elements;
• a history of Quincke edema that develops due to the use of aliskiren;
• idiopathic or hereditary form of Quincke edema;
• combining aliskiren with itraconazole or cyclosporin (they are inhibitors of the P-gp element with high efficacy), and in addition, other potent inhibitors of the P-gp component (eg, quinidine);
• combination of the drug with drugs blocking the conductors of angiotensin or with ACE inhibitors - people with diabetes mellitus or a disorder in the kidneys (GFR <60 ml / minute / 1.73 m ² );
• infants less than 2 years old.

Side effects of the racileza

The use of the drug can cause some side effects:

• immune reactions: occasionally there are anaphylactic manifestations and signs of hypersensitivity;
• balance and hearing organs: sometimes a vertigo may appear;
• disorders in the work of the heart: often there are dizziness; peripheral puffiness and tachycardia occur more rarely;
• reactions of the vascular system: occasionally a decrease in pressure is observed;
• organs of the respiratory system: there may be a cough;
• violations in the work of the digestive tract: often there is diarrhea. There may be vomiting or nausea;
• reactions of the hepatobiliary system: there may be disorders in the work of the liver, and in addition hepatitis, jaundice or liver failure;
• subcutaneous layers, and also the skin: skin manifestations occasionally develop, including Stevens-Johnson syndromes or Lyell's, itching and eruptions, as well as urticaria, and in addition to this manifestation in the oral mucosa. Sometimes it develops erythema or edema Quincke;
• reactions of connective tissue and ODA: arthralgia often appears;
• urinary system and kidneys: occasionally develop disorders of renal function or kidney failure in acute form;
• indications of laboratory tests: mainly observed hyperkalemia. The level of liver enzymes increases more rarely. Occasionally there is a decrease in the parameters of hemoglobin or hematocrit, and besides this increase in the values of creatinine inside the blood.

[3]

Dosing and administration

For a day it is recommended to take 150 mg of medicine once. Persons whose blood pressure can not be adequately controlled, it is permitted to increase the dose to a single dose of 300 mg per day.

The hypotensive effect of drugs develops in the period of 2 weeks (approximately 85-90%) from the moment of the beginning of the use of the drug in a single dose of 150 mg.

Racilus can also be taken in combination with other antihypertensive drugs (except for ACE inhibitors, as well as blockers of angiotensin II (BRA)) in people with diabetes mellitus or with kidney problems (GFR time is <60 ml / minute / 1 , 73 m ² ).

It is recommended to use the medicine together with light food. It is also advisable to take tablets at the same time every day. For the duration of the course of therapy with Racileuse, it is necessary to abandon the use of grapefruit juice.

[4], [5]

Overdose

There is only limited information about drug overdose. It can be assumed that the most likely outcome of an overdose will be a decrease in blood pressure, which is due to the hypotensive properties of aliskiren. With the development of symptomatic pressure reduction, supportive therapy should be provided.

Interactions with other drugs

Clinical tests have demonstrated that the drug does not have a pharmacokinetic interaction with the following substances: celecoxib with acenocoumarol, as well as allopurinol and atenolol with pioglitazone and hydrochlorothiazide with isosorbide-5-mononitrate.

Individual drugs in combination with aliskiren can change its peak level (within 20-30%) or AUC. Among those - metformin (reduces the peak value by 28%), amlodipine (a decrease of 29%) and cimetidine (increases by 19%).

The combination with atorvastatin resulted in an increase in peak values and a drug AUC level of 50%. Racilus does not have a significant effect on the pharmacokinetic characteristics of metformin, atorvastatin, and amlodipine. As a result, when these drugs are combined with aliskiren, correction of their dosage is not required.

Admission with Racileus may slightly lower the level of bioavailability of the digoxin substance.

Preliminary information indicates that irbesartan is capable of decreasing the peak values and AUC of the drug.

Interaction with the CYP450 element.

The active substance does not inhibit the isoenzymes CYP450 (also CYP1A2 with 2C8, as well as 2C9 and 2C19 with 2D6, 2E1 with 3A). In addition, it does not induce the element CYP3A4. As a consequence, there is no reason to expect that aliskiren will affect the AUC of drugs that are induced, slowed down or metabolized with the participation of these enzymes.

Aliskiren undergoes minimal metabolism with the help of enzymes of the hemoprotein P450, which is why interaction is not expected after the inhibition or stimulation of isoenzymes CYP450. But inhibitors of the element CYP3A4 quite often affect P-gp. This allows one to expect an increase in the AUC of aliskiren during the period of combined use with inhibitors of the CYP3A4 element, which slow down the effect of P-gp.

Interaction with the P-gp element.

With preclinical testing, MDR1 / Mdr1a / 1b (P-gp) was found to be the main efflux system for intestinal absorption, as well as biliary excretion of aliskiren. Clinical tests have shown that rifampicin (an inductor of the P-gp element) reduces the level of bioavailability of aliskiren by approximately 50%. Other inducers of P-gp substance (such as St. John's Wort) are also able to lower the bioavailability of the drug.

Although such studies have not been carried out with aliskiren, it is known that the P-gp element also plays a major role in the capture of various substrates by tissues, and substances that slow P-gp are capable of increasing the tissue-plasma ratio. This allows the inhibitors of the P-gp component to more strongly influence the indices of the drug inside the tissues (increasing them) than the plasma values. The potential for drug interaction in the P-gp region will most likely depend on the level of suppression of this vector.

Substrates or drugs that slow P- gp (with poor efficacy).

There is no significant interaction with substances digoxin, cimetidine, as well as amlodipine or atenolol. After combining with atorvastatin (at a dose of 80 mg), the steady-state values of peak indices and the level of AUC of aliskiren (at a dose of 300 mg) were increased by 50%. Animal tests have demonstrated that P-gp is the main determining factor that allows you to know the level of bioavailability of Racileuse.

Medications with a moderate retardation effect on P- gp.

The combination of the drug (300 mg) with ketoconazole (200 mg) or verapamil (240 mg) caused an increase in its peak plasma values (by 97%) and AUC (by 76%). It should be expected that the values of aliskiren inside the plasma in combination with verapamil or ketoconazole will vary within the same limits as due to the use of a double dose of Racilease. Clinical tests showed that aliskiren in dosages of up to 600 mg (2 times the recommended value) was tolerated without adverse consequences.

Preclinical tests demonstrated that the combination of drugs with ketoconazole enhances the absorption of aliskiren from the gastrointestinal tract, and also weakens the biliary excretion of the substance. But it is expected that the use of P-gp inhibitors will increase the concentration of the substance inside the tissues more than the plasma. In this regard, it is necessary to carefully mix the drug with ketoconazole or other P-gp (moderate effect) inhibitors such as telithromycin, amiodarone, and erythromycin with clarithromycin.

Medications that slow down P- gp (with a powerful effect).

Tests on the interaction of single doses in volunteers demonstrated that cyclosporine (in dosages of 200 and 600 mg) increased the peak level of aliskiren (75 mg) approximately 2.5-fold, and the AUC-value approximately 5-fold. An increase can also occur with higher doses of aliskiren.

Itraconazole at a dose of 100 mg increased the peak values of the drug (150 mg) by 5.8 times, as well as the level of its AUC (by 6.5 times) in volunteers. Because of this, the reception of Racilez in combination with powerful inhibitors of P-gp is prohibited.

Inhibitors of polypeptide carriers of organic anions.

Preclinical testing makes it clear that aliskiren can become a TPOA substrate, which suggests that there is a potential for its interaction with TPAO inhibitors when combining these drugs.

Torasemide with furosemide.

Combined ingestion of furosemide and aliskiren does not affect the pharmacokinetic characteristics of the latter, but the effect of furosemide is weakened by about 20-30% (studies on the effect of aliskiren on furosemide administered in / or in / m were not performed).

With repeated use of furosemide (60 mg daily) in combination with aliskiren (300 mg daily), the excretion of sodium in urine decreased in the first 4 hours, and in addition, urine volume (by 31% and 24% ) in comparison with the situations when only furosemide was used. The average weight of people taking aliskiren (300 mg) with furosemide exceeded the weight values of people taking only furosemide (84.6 / 83.4 kg).

When using the drug at a dose of 150 mg, there were insignificant changes in the efficacy and pharmacokinetic indices of furosemide.

In existing clinical information, there is no information on the combination of aliskiren with torasemide in high doses. It is known that the excretion of torasemide through the kidney occurs with the indirect participation of carriers of organic anions. Minimal doses of aliskiren are excreted through the kidneys, and only 0.6% of the dosage of the substance can be observed in the urine when ingestion is given. But, since it is revealed that aliskiren is a substrate for the polypeptide carrier of organic anions 1A2 (OATP1A2), it is potentially possible to lower the plasma level of torasemide under the influence of aliskiren (it affects the absorption process).

In patients who use aliskiren with torasemide or furosemide (orally), it is required to carefully monitor the effects of these substances at the beginning of treatment or when adjusting the doses of the above drugs. This is necessary to avoid changes in the volume of intercellular fluids, as well as possible volume overload.

Use in combination with NSAIDs.

As with the use of other drugs that affect the function of PAC, in the case of NSAIDs, it is possible to weaken the hypotensive properties of aliskiren.

In some people with disorders in the work of the kidneys (elderly patients, dehydration) a combination of such drugs can contribute to a subsequent deterioration in the work of the kidneys (for example, acute insufficiency, often this pathology is reversible). Therefore, it is required to combine the drug data with caution (especially for the elderly).

Medicines affecting serum potassium levels.

With the simultaneous use of Racileuse with potions such as potassium-sparing diuretics, dietary potassium supplements, salt substitutes, which contain calcium, and other substances that can affect potassium levels (eg heparin), potassium may increase. If this treatment is necessary, it should be done with great care.

With a double blockade of the function of RAAS BRA, aliskiren or ACE inhibitors.

The results of clinical tests demonstrated that with double blockade of the function of RAAS by the combined use of aliskiren with ARB or ACE inhibitors, the incidence of side effects (such as stroke, pressure decrease, renal function impairment (eg acute kidney failure) and hyperkalemia ) compared with monotherapy with the use of only ARBs.

[6], [7], [8], [9]

Storage conditions

Racial is necessary to store in a place where moisture does not penetrate, and in addition to inaccessible children. Temperature values are a maximum of 30 ° C.

[10], [11], [12]

Shelf life

Racialosis can be used in the 2 years since the manufacture of the medicine.

[13]