Universal reference book for medicines
Product name: ADEMPAS (ADEMPAS)

Active substance: riociguat

Type: Guanylate cyclase stimulant.
The drug used for pulmonary hypertension
Manufacturer: BAYER PHARMA (Germany) manufactured by BAYER PHARMA (Germany) packed by STEGEMANN LOHNVERPACKUNG & LOGISTISCHER SERVICE (Germany)
Composition, form of production and packaging
The tablets covered with a film shell of
white color, round, biconcave, on one side the method of extrusion is marked "R" and "0.5", on the other side the Bayer logo in the form of a cross.

1 tab.

riotsiguat micronized 0.5 mg

Excipients: microcrystalline cellulose - 35 mg, crospovidone - 6 mg, hypromellose 2910 - 3 mg, lactose monohydrate - 39.8 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.1 mg.

The composition of the film shell: giprolose - 1.1 mg, hypromellose 2910 - 0.36 mg, propylene glycol - 0.21 mg, titanium dioxide - 0.83 mg.

21 pcs.
- blisters (2) - packs of cardboard.
21 pcs.
- blisters (4) - packs of cardboard.
The tablets covered with a film cover of pale yellow color, round, biconcave, on one side by a method of squeezing out it is put "R1", on other side the logo of company Bayer in the form of a cross.

1 tab.

riotsiguat micronized 1.0 mg

Excipients: microcrystalline cellulose - 35 mg, crospovidone - 6 mg, hypromellose 2910 - 3 mg, lactose monohydrate - 39.2 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.2 mg.

The composition of the film shell: giprolose - 1.1 mg, hypromellose 2910 - 0.36 mg, propylene glycol 0.21 mg, titanium dioxide 0.82 mg, iron oxide yellow oxide 0.01 mg.

21 pcs.
- blisters (2) - packs of cardboard.
21 pcs.
- blisters (4) - packs of cardboard.
The tablets covered with a film cover of yellow color, round, biconcave, on one side the method of extrusion is marked "R" and "1.5", on the other side the Bayer logo in the form of a cross.

1 tab.

riotsiguat micronized 1.5 mg

Excipients: microcrystalline cellulose - 35 mg, crospovidone - 6 mg, hypromellose 2910 - 3 mg, lactose monohydrate - 38.7 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.2 mg.

The composition of the film shell: giprolose - 1.1 mg, hypromellose 2910 - 0.36 mg, propylene glycol - 0.21 mg, titanium dioxide - 0.73 mg, iron oxide oxide yellow - 0.1 mg.

21 pcs.
- blisters (2) - packs of cardboard.
21 pcs.
- blisters (4) - packs of cardboard.
The tablets covered with a film cover of pale orange color, round, biconcave, on one side by a method of squeezing out it is put "R2", on other party the logo of company Bayer in the form of a cross.

1 tab.

riotsiguat micronized 2.0 mg

Excipients: microcrystalline cellulose - 35 mg, crospovidone - 6 mg, hypromellose 2910 - 3 mg, lactose monohydrate - 38.2 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.2 mg.

The composition of the film shell: giprolose - 1.1 mg, hypromellose 2910 - 0.36 mg, propylene glycol - 0.21 mg, titanium dioxide - 0.61 mg, iron dye oxide yellow 0.2 mg, iron oxide red oxide 0.02 mg.

21 pcs.
- blisters (2) - packs of cardboard.
21 pcs.
- blisters (4) - packs of cardboard.
The tablets, covered with a film coating of brownish-orange color, are round, biconvex, on one side the method of extrusion is marked "R" and "2.5", on the other side the Bayer logo in the form of a cross.

1 tab.

riotsiguat micronized 2.5 mg

Excipients: microcrystalline cellulose - 35 mg, crospovidone - 6 mg, hypromellose 2910 - 3 mg, lactose monohydrate - 37.7 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.2 mg.

The composition of the film shell: giprolose - 1.1 mg, hypromellose 2910 - 0.36 mg, propylene glycol 0.21 mg, titanium dioxide 0.35 mg, iron oxide, yellow 0.4 mg, iron oxide red 0.08 mg.

21 pcs.
- blisters (2) - packs of cardboard.
21 pcs.
- blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

Hypotensive agent, a stimulator of guanylate cyclase .

Mechanism of action

Riotsiguat is a stimulant of soluble guanylate cyclase (rGTs), an enzyme of the cardiopulmonary system and a nitric oxide receptor (NO).

In the binding of NO to the rGTs, the enzyme catalyzes the synthesis of the signaling molecule of cyclic guanosine monophosphate (cGMP).
Intracellular cGMP plays an important role in the regulation of processes that affect vascular tone, proliferation, fibrosis and inflammation.
Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the metabolic pathway of NO-rGT-cGMP.
Rioziguat has a dual mechanism of action. It sensitizes cGMP to endogenous NO by stabilizing NO-cGMP binding. The riotsiguat also directly stimulates the RHC through another link, regardless of NO.
Rioziguat restores the metabolic pathway of NO-rGT-cGMP and causes an increase in cGMP production.

Efficacy in patients with chronic thromboembolic pulmonary hypertension (CTEPH)

Efficacy was assessed in a randomized, double-blind, international multicenter, placebo-controlled Phase III trial (CHEST-1) that included inoperable patients or patients with persistent and / or recurrent CTEPH after pulmonary endarterectomy (group 4, according to the World Health Organization, WHO).
The study included 261 patients with different severity of the disease (functional classes, PK), of which 31% of patients belong to the II functional class according to the WHO classification (WHO FC I), 64% - WHO FC III, with an average distance in test 6 -minute walk (6MHT, 150-450 m) 347 m.
The primary end point of effectiveness: a change in the distance in 6MHT by week 16 compared with the original

In the course of treatment, the following results were achieved:

- a change in the 6MHT distance to 16 weeks in the riotsiguata group by 46 m compared with placebo (p <0.0001);

- a significant reduction in pulmonary vascular resistance (LSS) p <0.0001, placebo-adjusted mean change from the initial -246 dyne / s-cm -5 ;
95% confidence interval (CI) from -303 to -190; p <0.0001;
- a significant reduction in the N-terminal fragment of the medulla natriuretic peptide (NT-proBNP), a placebo-adjusted mean change from baseline -444 ng / l, CI -843 to -45 in the riotsiguata group compared with placebo;

- significant improvement, at least one FC, at 16 weeks in the riotsiguata group in 33% of patients, in the placebo group - 15%;
reduction of at least one FC in 5% of patients in the riotsiguata group, 7% in the placebo group (p = 0.0026). FK was unchanged in 62% of patients in the riotsiguata group, 78% in the placebo group.
There was an improvement in hemodynamic parameters in the riotsiguata group compared with placebo: a statistically significant decrease in LSS, mean pulmonary artery pressure (minus 5.0 mm Hg, p <0.0001) and an increase in cardiac index (SI) by 0.47 l / min / m 2 ;
(p <0.0001).
Long-term treatment with HTEPH (CHEST-2) included 237 patients who completed the CHEST-1 study.
The average duration of treatment at the time of data cutting is 388 days. In the CHEST-2 study, further improvements were observed from the 6MHT and FK distance. Annual survival rate is 98%.
Efficacy in patients with pulmonary arterial hypertension (PAH)

Efficacy was assessed in a randomized, double-blind, international multicenter, placebo-controlled, Phase III (PATENT-1) study, in which 443 patients participated (initial clinical status: 42% of FC II, 54% of WHO FC III, mean distance 6MHT 150-450 m) 363 m) who were not treated, or who received therapy with endothelin receptor antagonists (ERAs) or prostacyclin analog (AP) (inhalation, inward or subcutaneously).
The population of the patients included men and women between the ages of 18 and 80; 61% idiopathic PAH, 2% hereditary PAH, 25% PAH associated with connective tissue diseases, 8% PAH associated with congenital heart disease, 3% PAH associated with portal hypertension, 1% LAH, associated with the reception of anorectics or amphetamine (group 1 according to WHO classification).
Primary endpoint of effectiveness: change of distance in 6MHT by 12th week

In the course of treatment, the following results were achieved:

- change of the 6MHT distance to 12 weeks in the riotsiguata group by 36 m compared with placebo (p <0.0001);

- a significant decrease in LSS p <0.0001, a placebo-adjusted mean change from the initial -226 dyne-s-cm -5 ;
95% CI from -281 to -170; p <0.0001;
- significant decrease in NT-proBNP placebo-adjusted mean change from baseline -432 ng / l, 95% CI from -782 to -82 in the riotsiguata group compared with placebo;

- Significant improvement in at least one FC in the riotsiguata group in 21% of patients, in the placebo group - 14%;

- delay in clinical deterioration in time was noted in the riotsiguata group (p = 0.0046, stratified log-rank test);

- significantly fewer clinical manifestations at 12 weeks in the riotsiguata group (1.2%) compared with placebo (6.3%) (p = 0.0285, Mantel-Hansel test);

- assessment of dyspnea on the Borg scale: significant improvement (-0.4 for riotsiguata in comparison with +0.1 for placebo, p = 0.0022).

There was an improvement in hemodynamic parameters in the riotsiguata group compared with placebo: SDL (minus 3.8 mmHg, p <0.0001) and an increase in SI (by 0.56 l / min / m 2 , p <0.0001).

Long-term treatment of PAH (PATENT-2) included 363 patients who completed the PATENT-1 study.
The average duration of treatment at the time of data cutting is 438 days. In the PATENT-2 study, further improvements from the 6MHT and FK distance were observed. The annual survival rate is 96%.
PHARMACOKINETICS

Suction

Absolute bioavailability of riotsiguata is high (94%).
The riotsiguat is rapidly absorbed, C max in the blood plasma is reached after 1-1.5 h after ingestion. Absorption of riotsiguata occurs throughout the gastrointestinal tract, mainly in the upper parts. In the distal parts of the gastrointestinal tract, absorption decreases. The use of the drug at the same time as food intake did not affect the value of AUC riotsiguata, C max was reduced to the minimum limit (a decrease of 35%). This change is considered clinically insignificant.
Distribution

Binding to blood proteins is high and is approximately 95%.
The main binding components are serum albumin and alpha 1- acid glycoprotein.
V d is average, while in the equilibrium state it is approximately 30 liters.

Metabolism

N-demethylation catalyzed by the isoenzymes CYP1A1, CYP3A4, CYP2C8 and CYP2J2 is the main pathway of the metabolism of riotsiguata, leading to the formation of its main circulating metabolite (pharmacological activity: from 1/10 to 1/3 of the rhyociguate), which is further metabolized into a pharmacologically inactive N -glucuronide.

The CYP1A1 isozyme catalyzes the formation of the main metabolite of riotsiguata in the liver and lungs.
This process is enhanced by polycyclic aromatic hydrocarbons, for example, contained in cigarette smoke.
Excretion

T 1/2 is approximately 7 hours in healthy volunteers and about 12 hours in patients.
All riotsiguat (the original drug and metabolites) is excreted by the kidneys (33-45%) and through the intestine (48-59%). From 4 to 19% of the administered dose is excreted unchanged by the kidneys, approximately 9-44% through the intestine.
Based on in vitro data, riotsiguat and its main metabolite are found to be substrates for transport proteins P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein).
Rioziguat is a preparation with low clearance (systemic clearance is approximately 3-6 l / min).
Pharmacokinetics in specific patient groups

Older patients (65 years of age and older) had a higher concentration of riotsiguata in the blood plasma than in the young, while the AUC were approximately 40% higher in the elderly, mainly due to an apparent decrease in total and renal clearance.

In patients with cirrhosis of the liver accompanied by mild hepatic insufficiency (5-6 points on the Child-Pugh scale, class A), there were no clinically significant changes in the effect of the drug.
In patients with hepatic cirrhosis accompanied by moderate hepatic insufficiency (7-9 points on the Child-Pugh scale, grade B), the average AUC of the rhyocyclate increased by 50-70% compared to healthy volunteers from the control group. The use of riotsiguata in patients with severe hepatic insufficiency (10-15 points on the Child-Pugh scale, class C) is contraindicated, since there are no clinical data for such patients.
In patients with renal insufficiency
in comparison with patients with normal renal function, the average values ​​of the normalized dose and intensity of the action of riotsiguata were higher. Corresponding indices for the main metabolite were higher in patients with renal insufficiency in comparison with healthy volunteers. In patients with CC 80-50 ml / min, 49-30 ml / min and less than 30 ml / min, the concentration of riotsiguata in blood plasma (AUC) increased by 43%, 104% or 44%, respectively. No data are available for patients with CC <15 mL / min or who are on hemodialysis. Therefore, the use of the drug is contraindicated in patients with CC <15 ml / min or who are on hemodialysis.
Since riotsiguat has a high degree of binding to blood plasma proteins, the possibility of removing it with dialysis seems unlikely.

There were no significant differences in the effectiveness of riotsiguata depending on the sex, ethnic group or body weight of the patient.

INDICATIONS

Chronic thromboembolic pulmonary hypertension (CTEPH), group 4 according to WHO classification:

- Inoperable HTELG;

- persistent or relapsing CTEPH after surgical treatment.

Pulmonary arterial hypertension (LAS), group 1 according to WHO classification, II-III FC according to WHO classification (in monotherapy or in combination with endothelin receptor antagonists or prostanoids):

- Idiopathic PAH;

- hereditary PAH;

- LAS, associated with connective tissue diseases.

DOSING MODE

The drug is taken orally.
Adempas can be taken with meals or whatever time you eat.
Initiation of therapy

The recommended initial dose is 1 mg 3 times / day for 2 weeks.
Tablets should be taken 3 times / day at intervals of about 6-8 hours, at the same time as eating or regardless of the time of ingestion.
With systolic blood pressure, 95 mm Hg.
and the absence of symptoms of arterial hypotension, the dose should be increased by 0.5 mg every 2 weeks to a maximum daily dose of 2.5 mg 3 times / day.
With systolic blood pressure <95 mm Hg.
and if there are no symptoms of arterial hypotension, the dose should be kept the same .
If, at any time during the titration phase, the systolic blood pressure is <95 mm Hg.
and at the same time signs of arterial hypotension are noted, the current single dose should be reduced by 0.5 mg, i.e. recommend the appointment of a previously accepted and well tolerated dose.
Maintenance dose

The dose should be maintained, unless symptoms of arterial hypotension develop.

The maximum daily dose of Adempas is 7.5 mg.

In case of missing the next dose of the drug, the next dose should be taken in accordance with the prescribed scheme of use.

In case of development of undesirable reactions after application of the prescribed dose of the drug, the dose may be reduced at any time of treatment.

Cancellation treatment

If there is a need for a break in treatment for 3 days or more, you should return to the initial dose and resume taking the drug, starting at a dose of 1 mg 3 times / day for 2 weeks;
then continue treatment, followed by titration of the dose, as described above.
Special patient groups

The safety and efficacy of Adempas have not been studied in patients under the age of 18 years .
Since there are no available data on the use of the drug in children, Adempas is contraindicated in patients under the age of 18 years.
In elderly patients (65 years and older) , special care should be taken when selecting a dose.

In patients with impaired renal function (CC less than 80 ml / min, but more than 15 ml / min), a more pronounced effect of the drug Adempas was noted, therefore, when choosing a dose in such patients, special care should be taken.
Contraindicated the use of the drug Adempas in patients with severe renal dysfunction (CC less than 15 ml / min) or who are on hemodialysis , since studies in such patients have not been conducted.
Concentrations of riotsiguata in blood plasma in patients with mild violations of liver function (5-6 points on the Child-Pugh scale, class A) are similar to the concentrations of riotsiguata in blood plasma in healthy volunteers.
In patients with moderate impairment of liver function (7-9 points on the Child-Pugh scale, class B), the more pronounced effect of Adempas was noted. When choosing a dose in these patients should be very careful. The use of Adempas in patients with severe impairment of liver function (more than 9 points on the Child-Pugh scale, class C) is contraindicated, since. studies in this group of patients were not conducted.
Smoking patients are strongly advised to stop smoking because the concentration of riotsiguata in the blood plasma of smokers is significantly reduced compared to non-smokers.
If the patient begins or stops smoking during the treatment with Adempas, a dose adjustment may be required.
SIDE EFFECT

The adverse events presented below are listed according to the frequency of occurrence in clinical trials.
Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10 000 and < 1/1000), very rarely (<1/10 000).
Infectious and parasitic diseases: often - gastroenteritis.

From the blood and lymphatic system: often - anemia (including relevant laboratory parameters).
From the nervous system: very often - dizziness, headache.
Of the heart and blood vessels: often - increased heart rate, decreased blood pressure.
The respiratory system, organs, thoracic and mediastinal disorders: often - hemoptysis, epistaxis, nasal congestion; infrequently - pulmonary hemorrhage *.
On the part of the digestive tract: often - dyspepsia, diarrhea, nausea, vomiting; often - gastritis, GERD, dysphagia, pain in different parts of the gastrointestinal tract, constipation, bloating.
General disorders and administration together: very often - peripheral edema.
* Reported case of fatal pulmonary bleeding within the framework of long-term studies with no control group.
CONTRAINDICATIONS

- simultaneous with nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form;
- simultaneous application of drugs group phosphodiesterase inhibitors (PDEs), including: with drugs group PDE5 inhibitors such as sildenafil, vardenafil, tadalafil, or a group of drugs nonspecific PDE inhibitors, such as dipyridamole and theophylline;
- congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose);
- severe hepatic dysfunction (more than 9 points on a scale Child-Pugh Class C), as clinical experience with offline;
- severe hypotension at the beginning of therapy (systolic blood pressure less than 95 mmHg) as clinical use experience is absent);
- severe renal impairment (creatinine clearance less than 15 mL / min) and use in patients on hemodialysis (clinical use experience is absent);
- Pregnancy;

- the period of breast-feeding;
- age up to 18 years;

- Hypersensitivity to riotsiguatu or any other components that make up the drug.
With care should be prescribed in the following situations:
- in patients with pulmonary hypertension patients who have additional risk factors for bleeding from the respiratory tract, particularly in those receiving anticoagulant therapy;
- in patients receiving antihypertensive therapy, or in patients with underlying arterial hypotension, hypovolemia or severe obstruction otttoka tract of the left ventricle, or autonomic dysfunction;
- while the use of potent inhibitors isoenzyme CYP1A1, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as the immunosuppressive drug cyclosporin A;
- in patients with impaired renal function (creatinine clearance less than 80 mL / min but more than 15 ml / min);
- in patients with moderate hepatic impairment (7-9 points on a scale Child-Pugh Class C);
- in elderly patients (65 years and older).
PREGNANCY AND LACTATION

Adempas during pregnancy drug contraindications.
Adempas The drug should not be administered to women during lactation because of the potential for serious adverse reactions in children who are breastfed.Breastfeeding decision on the termination or cancellation, and / or abstinence during lactation should be based on an assessment of risk-benefit ratio.
In studies in rats were observed effects on male and female fertility. Embryotoxicity study of models in rats and rabbits showed reproductive toxicity riotsiguata. The study in rats was observed increased risk of heart disease, as well as reducing the frequency of pregnancy in an early resorption of the fetus with systemic effects on the mother's body, which is about 7 times larger than the effect in humans (2.5 mg 3 times / day). In a study in rabbits, since systemic exposure levels exceeding the human exposure to 3-fold (2.5 mg 3 times / day) were observed miscarriages and embryotoxicity.
Not conducted specific studies with riotsiguata to assess its impact on fertility in humans. During the treatment with Adempas women of childbearing age should use effective methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with renal impairment (creatinine clearance less than 80 mL / min but more than 15 ml / min) had a more pronounced effect Adempas formulation so requires special care in the selection of the dose in these patients.
Adempas not use this drug in patients with severe renal impairment (creatinine clearance less than 15 mL / min) or on hemodialysis because studies in such patients have not been conducted.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Riotsiguata concentration in blood plasma in patients with mild hepatic impairment (5-6 points on a scale Child-Pugh class A) are similar to concentrations riotsiguata in the blood plasma of healthy volunteers.
In patients with moderate hepatic impairment (7-9 points on a scale Child-Pugh Class B) had a more pronounced effect Adempas drug. In the selection of dose in these patients should be particularly careful.
Use of the drug Adempas in patients with severe hepatic impairment (more than 9 points on the Child-Pugh, class C) is contraindicated since studies in these patients have not been conducted.
APPLICATION FOR CHILDREN

The safety and efficacy Adempas drug has not been studied in patients under the age of 18 years. Since the available data on the use of the drug in children are not available, Adempas contraindicated in patients under the age of 18 years.
APPLICATION IN ELDERLY PATIENTS

Elderly patients (65 years and older) should be very careful in the selection of a dose.
SPECIAL INSTRUCTIONS

Venookklyuzionnaya pulmonary disease
Use of the drug in patients with Adempas venookklyuzionnoy pulmonary disease (Caspian roach) is not recommended as pulmonary vasodilators may significantly worsen the clinical condition of these patients. When the pulmonary edema symptoms should suggest the possibility of associated Voblyi. In this case, treatment with the drug should be discontinued Adempas.
Bleeding from the respiratory tract
in patients with pulmonary hypertension, there is an increased chance of bleeding from the respiratory tract, particularly in patients receiving anticoagulant therapy.
In treating drug Adempas risk of serious and / or fatal bleeding from the respiratory tract may increase, especially in the presence of risk factors such as recent episode severe hemoptysis, including its treatment with bronchial arterial embolization. Should regularly assess the risk-benefit ratio in each individual patient.
vasodilator effect
Preparation Adempas has vasodilating properties, which may lead to reduction in blood pressure. Prior to the appointment of the drug should carefully assess the risk of adverse effects of vasodilator in patients with concomitant diseases (eg, in patients receiving antihypertensive therapy, or with underlying arterial hypotension, hypovolemia, severe obstruction of the outflow tract of the left ventricle, or autonomic dysfunction).
Interactions with other drugs
Simultaneous use of the drug Adempas with powerful inhibitors of the cytochrome and P-gp / BCRP, such as the antifungal drugs from the group of azoles (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (such as Ritonavir), not recommended due to express amplification steps Adempas preparation.
Simultaneous use of the drug with potent inhibitors Adempas isoenzyme CYP1A1, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as the immunosuppressant cyclosporin A, may enhance the action Adempas preparation. These drugs should be used with caution. It is necessary to control the blood pressure and consider reducing the dose of the drug Adempas.
The patient population, the study, which were not carried out
Adempas has not been studied in the following groups of patients, and therefore, its use is contraindicated in them:
- Patients with systolic blood pressure less than 95 mmHg at the time of initiation of treatment;
- Patients with hepatic impairment, severe (more than 9 points on a scale Child-Pugh Class C);
- Patients with severe renal impairment (creatinine clearance less than 15 mL / min) or on hemodialysis.
Information for specific groups of patients
in smoking patients riotsiguata efficiency is reduced by 50-60%. Such patients are strongly encouraged to quit smoking.
Impact on the ability to drive vehicles and manage mechanisms

Reported cases of dizziness in some patients, so caution should be exercised when driving and operating other machines.
OVERDOSE

Symptoms

It reported unintentional overdose riotsiguata when used at a dose of 9-25 mg for 2-32 days. Adverse reactions were similar to those observed while taking the drug at lower doses.
Treatment

A specific antidote is not known. In case of overdose should apply the standard supportive measures, in accordance with the clinical need. When excessive decrease in blood pressure may require active hemodynamic support. Since riotsiguat has a high degree of binding to plasma proteins, the possibility of removing it using dialysis is unlikely.
DRUG INTERACTION

Pharmacokinetic interaction
Riotsiguat derived mainly by oxidative metabolism mediated by the cytochrome P450 system isoenzymes (isozymes CYP1A1, CYP3A4, CYP2C8, CYP2J2) , as well as in an unmodified form through the intestine or kidneys glomerular filtration process. It was identified on the basis of in vitro studies that riotsiguat is a substrate for membrane transport proteins P-gp / BCRP (P-glycoprotein / protein resistance of breast cancer). Inhibitors or inducers of these enzymes and / or transport proteins may affect the efficiency of riotsiguata.
In vitro it was shown that ketoconazole (CYP3A4 inhibitor and potent P-gp) is an inhibitor of multiple metabolic pathways involving CYP systems and P-gp / BCRP, involved in the metabolism and excretion riotsiguata. The simultaneous use of ketoconazole at a dose of 400 mg 1 time / day resulted in an increase of 150% (range up to 370%) and the mean AUC riotsiguata increase in C max by 46%. The final T 1/2 was increased from 7.3 to 9.2 hours and total body clearance decreased riotsiguata from 6.1 to 2.4 l / h.
Thus it is not recommended that the simultaneous use of the drug Adempas with potent inhibitors of multiple metabolic pathways involving cytochrome and P-gp / BCRP, such as the antifungal drugs from the group of azoles (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (e.g., ritonavir) .
Formulations significantly inhibit P-gp / BCRP, such as the immunosuppressant Cyclosporin A should be used with caution.
From recombinant cytochrome P450 isozymes examined in vitro, CYP1A1 most effectively catalyzed the formation of the major metabolite riotsiguata. Formulations class of tyrosine kinase inhibitors are potent inhibitors of isoenzyme CYP1A1, wherein erlotinib and gefitinib exhibited the greatest inhibiting activity in vitro. Thus, the simultaneous application of drugs, which are inhibitors of CYP1A1 may lead to increased riotsiguata effect, particularly in smoking patients. Therefore, strong CYP1A1 inhibitors should be used with caution.
The simultaneous use of clarithromycin (500 mg, 2 times / day) attributable to strong inhibitors of CYP3A4, is also an inhibitor of P-gp, moderately raised riotsiguata mean AUC by 41% without a significant change in C max. Such changes are clinically significant.
Concomitant use of drugs that increase the pH of the gastrointestinal tract, could result in lower bioavailability when administered as significantly lower solubility riotsiguata at neutral pH compared with the acidic medium.
Purpose before and during therapy riotsiguatom proton pump inhibitor omeprazole (40 mg 1 time / day) reduced the mean AUC riotsiguata 26%, and the average Cmax by 35%. These changes are clinically insignificant.
Antacids should be taken at least one hour after receiving riotsiguata, since simultaneous use of antacids based on aluminum hydroxide and / or magnesium hydroxide riotsiguata reduces the average AUC of 34% and an average C max by 56%.
Bosentan, which is a moderate inhibitor of CYP3A4, causes decreased C ss riotsiguata in the blood plasma of patients with PAH by 27% without impacting on the efficiency of the combination.
Simultaneous application riotsiguata and strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, phenobarbital or preparations containing St. John's wort) may also lead to a reduction riotsiguata concentration in blood plasma.
Effect riotsiguata other drugs
Riotsiguat and its major metabolite are neither inhibitors nor major inducers of cytochrome P450 isoenzymes (including CYP3A4) or transport proteins (e.g., P-gp / BCRP) at therapeutic concentrations under conditions in vitro.
The lack of pharmacokinetic interaction between riotsiguatom and CYP3A4 marker substrate midazolam was demonstrated in vivo.
It was found that in vitro riotsiguat and its major metabolite are potent inhibitors of CYP1A1. Thus, one can not exclude a clinically significant drug interactions with drugs taken at the same time, which largely derived by metabolism mediated by CYP1A1, such as erlotinib or granisetron.
Pharmacodynamic interaction
Nitrates
Simultaneous application riotsiguata and nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form is contraindicated because when applying riotsiguata 2.5 mg in the form of tablets, film-coated, were increased hypotensive effect of nitroglycerin (0.4 mg sublingual) received via 4 and 8 h after administration riotsiguata.
Inhibitors of PDE-5
in animal studies have demonstrated a decrease in systemic blood pressure when combined with riotsiguata sildenafil or vardenafil. When used in increased doses was observed in some cases an additional reduction in systemic blood pressure.
In ekstropolyatsionnom drug interaction study involving seven patients with PAH receiving chronic treatment with sildenafil (20 mg 3 times / day), riotsiguata single dose (0.5 mg and 1 mg in sequence) led to the summation effect of drugs on hemodynamics. Doses riotsiguata than 1 mg in this study were not studied.
12-week study using a combination of stable doses of sildenafil (20 mg 3 times / day) and riotsiguata (at a dose of 1-2.5 mg 3 times / day) compared with monotherapy sildenafil in 18 patients with PAH was conducted. In the extended phase of the study (in the absence of the control group) and the simultaneous application riotsiguata sildenafil led to a higher frequency cancellation riotsiguata, mainly du
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