Rasilez

Rasilez is a renin inhibitor drug.

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Indications Rasileza

Used to reduce blood pressure in the development of hypertension.

Release form

Release in tablets; 7 pieces per blister. Inside a separate package there are 2 or 4 blister plates. It can also be released with 14 tablets per blister; in this case, 1 or 2 such blister plates are put into the pack.

Rasilez nst

Rasilez NST is a drug that acts on the RAS. The drug is combined with hydrochlorothiazide.

It is used to treat primary hypertension in individuals with inadequate blood pressure control (when using monotherapy with aliskiren or hydrochlorothiazide) or in individuals with adequate blood pressure control (when using hydrochlorothiazide with aliskiren, which are taken in combination – in doses similar to those observed with the combination drug).

Pharmacodynamics

Aliskiren is a potent non-peptide human renin inhibitor (direct selective agent with potent action).

By inhibiting the enzyme renin, the active substance aliskiren inhibits the RAA system immediately at the moment of its activation. This occurs by blocking the process of converting the element angiotensinogen into angiotensin I, and along with this, reducing the indicators of angiotensin I, as well as II.

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

Pharmacokinetics

After administration of the drug, aliskiren is absorbed with a peak level reached after 1-3 hours. The bioavailability of the substance is approximately 2-3%. It should be taken into account that excessively fatty food reduces the peak level by 85%, and the AUC by 70%.

Steady-state plasma levels are observed 5-7 days after a single daily dose. Steady-state values of Rasilez are approximately twice those obtained after the initial dose.

Preclinical testing has shown that MDR1/Mdr1a/1b (P-glycoprotein) is the major efflux system involved in the intestinal absorption and biliary elimination of aliskiren.

After tablet administration, the mean distribution volume (steady-state value) is approximately 135 L, indicating that the active component of the drug is well distributed in the extravascular environment.

The synthesis of the component with plasma protein is quite moderate (about 47-51%). Concentration indicators do not affect it.

The half-life is approximately 40 hours (range 34-41 hours). Aliskiren is excreted mostly unchanged in feces (78%). About 1.4% of the total drug dose undergoes metabolism (CYP3A4 enzyme is responsible for it). After oral administration, 0.6% of the dose is found in the urine. The average clearance rate with intravenous injection is approximately 9 L/hour.

Exposure parameters of aliskiren increase more than proportionally with increasing dose. In the single dose range of 75-600 mg, doubling the dose resulted in increases in peak level and AUC (2.6- and 2.3-fold, respectively).

Nonlinearity of the drug at steady-state parameters may be even more pronounced. It was not possible to establish the mechanism that causes deviations in the linearity of the drug. The reason may be saturation of carriers at the absorption site or the hepatobiliary excretion pathway.

Dosing and administration

It is recommended to take 150 mg of the drug once a day. People whose blood pressure cannot be adequately controlled are allowed to increase the dose to a single dose of 300 mg per day.

The hypotensive effect of the drug develops within 2 weeks (approximately 85-90%) from the start of taking the drug in a single dose of 150 mg.

Rasilez can also be taken in combination with other antihypertensive drugs (the only exceptions are ACE inhibitors, as well as angiotensin II receptor blockers (ARBs) in people with diabetes mellitus or with kidney problems (SCF time is <60 ml/minute/1.73 m2 ⁾.

It is recommended to take the medicine with light food. It is also advisable to take the tablets at the same time every day. During the course of Rasilez therapy, it is necessary to refrain from drinking grapefruit juice.

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Use Rasileza during pregnancy

There is no information on the use of the substance in pregnant women. Rasilez did not have a teratogenic effect when tested on animals. Other drugs that have a direct effect on the function of the RAAS have caused the development of serious congenital anomalies, as well as death of newborns.

Like other drugs that directly affect the RAAS, Rasilez should not be used during pregnancy planning or in the 1st trimester. It is also contraindicated in the 2nd and 3rd trimesters. When prescribing any drug from the above group, it is necessary to warn those planning a pregnancy about the possible risk of complications when using the drug during pregnancy. It is necessary to cancel the drug if pregnancy is detected during therapy.

There is no information about aliskiren entering breast milk, therefore, taking the drug during breastfeeding is prohibited.

Contraindications

The main contraindications are:

• hypersensitivity to the active component of the drug or any of its additional elements;
• history of angioedema resulting from the use of aliskiren;
• idiopathic or hereditary form of Quincke's edema;
• combination of aliskiren with itraconazole or cyclosporine (they are highly effective inhibitors of the P-gp element), as well as other potent inhibitors of the P-gp component (for example, with quinidine);
• combination of the drug with drugs that block angiotensin conductors or with ACE inhibitors - for people with diabetes mellitus or renal dysfunction (SCF <60 ml/minute/1.73 m2 ⁾;
• infants under 2 years of age.

Side effects Rasileza

The use of the drug may cause the appearance of certain side effects:

• immune reactions: anaphylactic reactions and signs of hypersensitivity occasionally occur;
• balance and hearing organs: vertigo may sometimes occur;
• disturbances in the functioning of the heart: dizziness is often observed; peripheral edema and tachycardia occur less frequently;
• reactions of the vascular system: a decrease in pressure is occasionally observed;
• respiratory system: cough may occur;
• Gastrointestinal disorders: diarrhea often occurs. Vomiting or nausea may occur;
• reactions of the hepatobiliary system: liver dysfunction may occur, as well as hepatitis, jaundice or liver failure;
• subcutaneous layers, as well as skin: occasionally, skin manifestations develop, including Stevens-Johnson or Lyell syndromes, itching and rashes, as well as urticaria, and in addition, manifestations in the oral mucosa. Sometimes erythema or Quincke's edema develops;
• reactions of connective tissues and musculoskeletal system: arthralgia often appears;
• urinary system and kidneys: occasionally, renal dysfunction or acute renal failure develops;
• laboratory test results: hyperkalemia is mostly observed. More rarely, the level of liver enzymes increases. Rarely, there is a decrease in hemoglobin or hematocrit levels, and in addition, an increase in creatinine levels in the blood.

Overdose

There is limited information on drug overdose. It can be assumed that the most likely outcome of an overdose is a decrease in blood pressure, which is due to the hypotensive properties of aliskiren. If symptomatic pressure reduction develops, supportive therapy should be administered.

Interactions with other drugs

Clinical tests have shown that the drug has no pharmacokinetic interaction with the following substances: celecoxib with acenocoumarol, as well as allopurinol and atenolol with pioglitazone and hydrochlorothiazide with isosorbide-5-mononitrate.

Certain drugs in combination with aliskiren can change its peak level (by 20-30%) or AUC. Among them are metformin (decreases peak value by 28%), amlodipine (decreases by 29%) and cimetidine (increases by 19%).

Combination with atorvastatin resulted in a 50% increase in peak values and AUC of the drug. Rasilez has no significant effect on the pharmacokinetic characteristics of metformin, atorvastatin, and amlodipine. As a result, no dosage adjustment is required when combining these drugs with aliskiren.

Taking with Rasilez may slightly reduce the level of bioavailability of the substance digoxin.

Preliminary data indicate that irbesartan may decrease peak and AUC values of the drug.

Interaction with the CYP450 element.

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

Aliskiren undergoes minimal metabolism by the enzymes of the hemoprotein P450, therefore, the development of interactions after inhibition or stimulation of CYP450 isoenzymes is not expected. However, inhibitors of the CYP3A4 element quite often affect P-gp. This allows us 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 action of P-gp.

Interaction with the P-gp element.

Preclinical testing has shown that MDR1/Mdr1a/1b (P-gp) is the major efflux system involved in intestinal absorption and biliary elimination of aliskiren. Clinical testing has shown that rifampicin (a P-gp inducer) reduces the bioavailability of aliskiren by approximately 50%. Other P-gp inducers (such as St. John's wort) can also reduce the bioavailability of the drug.

Although such studies have not been conducted with aliskiren, it is known that the P-gp component also plays a major role in tissue uptake of a variety of substrates, and that agents that inhibit P-gp can increase tissue-to-plasma ratios. This allows inhibitors of the P-gp component to have a greater effect on tissue drug levels (increasing them) than on plasma values. The potential for drug interactions at the P-gp site will likely depend on the level of inhibition of this transporter.

Substrates or drugs that inhibit P-gp (with weak efficacy).

No significant interactions were observed with digoxin, cimetidine, amlodipine or atenolol. After combination with atorvastatin (80 mg), the steady-state peak and AUC values of aliskiren (300 mg) increased by 50%. Animal studies have shown that P-gp is the main determinant of the bioavailability of Rasilez.

Drugs with moderate inhibitory effect on P-gp.

The combination of the drug (at a dose of 300 mg) with ketoconazole (at a dose of 200 mg) or verapamil (at a dose of 240 mg) caused an increase in its peak plasma values (by 97%) and AUC (by 76%). It is expected that the plasma values of aliskiren in combination with verapamil or ketoconazole will change in the same range as due to the use of a double dose of Rasilez. Clinical tests have shown that aliskiren in doses up to 600 mg (twice the recommended value) was tolerated without adverse effects.

Preclinical tests have shown that the combination of the drug 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 contributes more to an increase in the concentration of the substance inside the tissues than in plasma. In this regard, it is necessary to carefully combine the drug with ketoconazole or other P-gp inhibitors (with moderate effect) - such as telithromycin, amiodarone, as well as erythromycin with clarithromycin.

P-gp inhibitor drugs (potent).

Single dose interaction tests in volunteers showed that ciclosporin (200 and 600 mg) increased peak aliskiren levels (75 mg) by approximately 2.5-fold and AUC by approximately 5-fold. Increases may also occur with higher doses of aliskiren.

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

Inhibitors of polypeptide organic anion transporters.

Preclinical testing suggests that aliskiren is a substrate for TPOA, suggesting potential for interactions with TPOA inhibitors when these drugs are combined.

Torasemide with furosemide.

Combined oral administration of furosemide and aliskiren does not affect the pharmacokinetic characteristics of the latter, but the effect of furosemide is weakened by approximately 20-30% (studies on the effect of aliskiren on furosemide administered intravenously or intramuscularly have not been conducted).

When furosemide (60 mg per day) was administered multiple times in combination with aliskiren (300 mg per day) in patients with heart failure, urinary sodium excretion and urine volume were reduced in the first 4 hours (by 31% and 24%, respectively) compared to situations where furosemide alone was used. The average weight of patients taking aliskiren (300 mg) with furosemide was higher than that of patients taking furosemide alone (84.6/83.4 kg).

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

There is no information in the existing clinical data on the combination of aliskiren with torasemide in high doses. It is known that the excretion of torasemide through the kidneys occurs with the indirect participation of organic anion transporters. 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 taking the drug orally. However, since it has been found that aliskiren is a substrate for the organic anion transporter polypeptide 1A2 (OATP1A2), a decrease in the plasma level of torasemide under the influence of aliskiren is potentially possible (it affects the absorption process).

In patients taking aliskiren with torasemide or furosemide (orally), the effects of these agents should be closely monitored at the start of treatment or when adjusting the doses of the above drugs. This is necessary to avoid changes in interstitial fluid volumes and possible volume overload.

Use in combination with NSAIDs.

As with the use of other drugs that affect the RAS function, in the case of using NSAIDs, the hypotensive properties of aliskiren may be weakened.

In some people with kidney problems (elderly patients, dehydration), the combination of such drugs may contribute to subsequent deterioration in kidney function (for example, acute renal failure; this pathology is often reversible). As a result, these drugs must be combined with caution (especially in the elderly).

Drugs that affect serum potassium levels.

When Rasilez is used simultaneously with such agents as potassium-sparing diuretics, dietary potassium supplements, salt substitutes containing calcium, and other substances that can affect potassium levels (for example, heparin), potassium levels may increase. If such treatment is necessary, it should be carried out with great caution.

With dual blockade of RAAS function with ARBs, aliskiren or ACE inhibitors.

Results of clinical trials have shown that dual blockade of RAAS function by combining aliskiren with ARBs or ACE inhibitors increases the incidence of adverse events (such as stroke, hypotension, decreased renal function (e.g. acute renal failure) and hyperkalemia) compared to monotherapy using ARBs alone.

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Storage conditions

Rasilez should be stored in a place where moisture does not penetrate, and in addition, inaccessible to children. Temperature values - maximum 30 ° C.

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Shelf life

Rasilez can be used for a period of 2 years from the date of manufacture of the medicine.