Adempas (Adempas)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRiotsiguatRiotsiguat
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  • Adempas
    pills inwards 
    Bayer Pharma AG     Germany
    • Dosage form: & nbspfilm coated tablets
    Composition:

    One tablet film coated, 0,5 mg contains:

    Active substance: riotsiguat micronized 0,50 mg.

    Excipients: microcrystalline cellulose 35,00 mg; crospovidone 6,00 mg; hypromellose-2910 3,00 mg; lactose monohydrate 39.80 mg; magnesium stearate 0,60 mg; sodium lauryl sulfate 0,10 mg; film sheath: giprolase 1,10 mg, hypromellose-2910 0,36 mg, propylene glycol 0,21 mg, titanium dioxide 0,83 mg.

    One tablet film coated, 1,0 mg contains:

    Active substance: riotsiguat micronized 1,00 mg.

    Excipients: microcrystalline cellulose 35,00 mg; crospovidone 6,00 mg; hypromellose-2910 3,00 mg; lactose monohydrate 39,20 mg; magnesium stearate 0,60 mg; sodium lauryl sulfate 0,20 mg; film sheath: giprolase 1,10 mg, hypromellose-2910 0,36 mg, propylene glycol 0,21 mg, titanium dioxide 0,82 mg, iron oxide dye yellow 0,01 mg.

    One tablet film coated, 1,5 mg contains:

    Active substance: riotsiguat micronized 1,50 mg.

    Excipients: microcrystalline cellulose 35,00 mg; crospovidone 6,00 mg; hypromellose-2910 3,00 mg; lactose monohydrate 38.70 mg; magnesium stearate 0,60 mg; sodium lauryl sulfate 0,20 mg; film sheath: giprolase 1,10 mg, hypromellose-2910 0,36 mg, propylene glycol 0,21 mg, titanium dioxide 0,73 mg, iron oxide dye yellow 0,10 mg.

    One tablet film coated, 2,0 mg contains:

    Active substance: riotsiguat micronized 2,00 mg.

    Excipients: microcrystalline cellulose 35,00 mg; crospovidone 6,00 mg; hypromellose-2910 3,00 mg; lactose monohydrate 38,20 mg; magnesium stearate 0,60 mg; sodium lauryl sulfate 0,20 mg; film sheath: giprolase 1,10 mg, hypromellose-2910 0,36 mg, propylene glycol 0,21 mg, titanium dioxide 0,61 mg, iron oxide dye yellow 0,20 mg, iron oxide red dye 0,02 mg.

    One tablet film coated, 2,5 mg contains:

    Active substance: riotsiguat micronized 2,50 mg.

    Excipients: microcrystalline cellulose 35,00 mg; crospovidone 6,00 mg; hypromellose-2910 3,00 mg; lactose monohydrate 37,70 mg; magnesium stearate 0,60 mg; sodium lauryl sulfate 0,20 mg; film sheath: giprolase 1,10 mg, hypromellose-2910 0,36 mg, propylene glycol 0,21 mg, titanium dioxide 0,35 mg, iron oxide dye yellow 0,40 mg, iron oxide red dye 0,08 mg.

    Description:

    Film-coated tablets, 0.5 mg: round biconvex tablets coated with a film shell, white, on one side by extrusion method applied << R >> and "0.5",on the other side is the Bayer logo in the form of a cross.

    Film-coated tablets, 1.0 mg: round biconvex tablets coated with a film coating, pale yellow, on one side by the extrusion method is applied "R1", on the other side the Bayer logo in the form of a cross.

    Film-coated tablets, 1.5 mg: round biconvex tablets coated with a film coating, yellow, on one side by extrusion method deposited "R" and "1.5", on the other side of the logo of the company Bayer in the form of a cross.

    Film-coated tablets, 2,0 mg: round biconvex tablets coated with a film coat, pale orange, on one side by extrusion method deposited "R2", on the other side is the Bayer logo in the form of a cross.

    Film-coated tablets, 2,5 mg: round biconvex tablets coated with a film coat, brownish-orange in color, on one side by extrusion method deposited "R" and "2.5", on the other side of the Bayer logo in the form of a cross.

    Pharmacotherapeutic group:Hypotensive agent - guanylate cyclase stimulant
    ATX: & nbsp

    C.02.K.X   Other antihypertensive drugs

    C.02.K.X.05   Riotsiguat

    Pharmacodynamics:

    Mechanism of action

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

    When tying NO with 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 ΝΟ-rGT-cGMP. Riotsiguat has a double mechanism of action. It sensitizes cGMP to endogenous NO by stabilizing the connection NO-cGMP. Riotsiguat also directly stimulates the RHC through another link, regardless of NO.

    The riotsiguat restores the metabolic pathway ΝΟ-rHC-cGMP and causes an increase in cGMP production.

    Efficiency the patients with chronic thromboembolic pulmonary hypertension (CTEPH)

    Efficacy was assessed in a randomized, double-blind, multicenter, placebo-controlled trial III phase (CHEST-1), including inoperable patients or patients, with persistent and / or recurrent CTEPH after pulmonary endarterectomy (group 4, according to the classification of the World Health Organization, WHO). The study was included 261 patient with different severity of the disease (functional classes, FC), among them 31 % of patients are II functional class according to WHO classification (FC I WHO), 64 % - FC III WHO, with an average distance in a 6-minute walk test (6MHT, 150 - 450 m) 347 m.

    Primary endpoint of effectiveness: changing the distance in 6MHT to 16 week compared to the original

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

    - change in the distance 6МХТ to 16 week in the riotsiguata group on 46 m compared with placebo (p <0.0001);

    - a significant reduction in pulmonary vascular resistance (JICC) p <0.0001, placebo-adjusted mean change from baseline - 246 dyne * s * cm-5; 95% confidence interval (CI) from -303 before -190; p <0.0001;

    - a significant decrease Ν-terminal fragment of the brain natriuretic peptide (NT-proBNP), placebo-adjusted mean change from baseline -444 ng / l, CI from -843 before -45 in the riotsiguata group compared with placebo;

    - a significant improvement of at least one FC per 16 week in the riotsiguata group 33 % of patients in the placebo group - 15 %; decrease by at least one FC 5 % of patients in the riotsiguata group, 7 % in the placebo group (p = 0.0026). FC without change 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 (SLE) (minus 5,0 mmHg, p <0.0001) and an increase in cardiac index (SI) by 0,47 l / min / m2; (p <0.0001).

    Long-term treatment HTELG (CHEST-2) included 237 patients who completed the study CHEST-1. The average duration of treatment at the time of data cutting - 388 days. In the study CHEST-2 Further improvements from the 6MHT and FK distance were observed. Annual survival rate - 98 %.

    Efficacy in patients with pulmonary arterial hypertension (PAH)

    Efficacy was assessed in a randomized, double-blind, multicenter, placebo-controlled trial III phase (PATENT-1), in which it participated 443 patient (initial clinical status: 42 % FC II, 54 % FC III WHO classification, the average distance in 6MX T (150 - 450 m) 363 m) who were not treated, or

    who received therapy with endothelin receptor antagonists (ERAs) or prostacyclin analog (AP) (inhalation, inside or subcutaneously). The population of the patients included men and women aged from 18 before 80 years; 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 % - PAH associated with the intake of anorectics or amphetamine (group 1 according to WHO classification).

    Primary endpoint of effectiveness: changing the distance in 6MHT to 12 week

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

    - change the distance 6МХТ to 12 week in the riotsiguata group on 36 m compared with placebo (p <0.0001);

    - a significant decrease in LSS p <0.0001, a placebo-adjusted mean change from baseline -226 dyne * s * cm-5; 95 % CI of -281 before -170; p <0.0001;

    - a significant decrease NT-proBNP placebo-adjusted mean change from baseline -432 ng / l, 95 % CI of -782 before -82 in the riotsiguata group compared with placebo;

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

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

    - significantly fewer manifestations of clinical impairment 12 week in the riotsiguata group (1,2 %) versus placebo (6,3 %) (p = 0.0285, the 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: SDLA (minus 3,8 mm Hg, p <0.0001) and an increase in SI (at 0,56 l / min / m2; p <0.0001).

    Long-term treatment LAS (PATENT-2) included 363 patient who completed the study PATENT-1. The average duration of treatment at the time of data cutting - 438 days. In the study PATENT-2 Further improvements from the 6MHT and FK distance were observed. Annual survival rate - 96 %.

    Pharmacokinetics:

    Suction

    Absolute bioavailability of riotsiguata high (94 %). Riotsiguat quickly absorbed, the maximum concentration in the blood plasma (Cmax) is achieved through 1-1,5 hours after ingestion. Absorption of riotsiguata occurs throughout the gastrointestinal tract (GIT), mainly in the upper sections. 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 the area under the pharmacokinetic curve "concentration-time" (AUC) riotsiguata, Cmax decreased to the minimum limit (decrease by 35 %). This change is considered clinically insignificant.

    Distribution

    Communication with blood proteins is high and is approximately 95 %. The main binding components are serum albumin and alpha-1acid glycoprotein.

    The volume of distribution is average, while in the equilibrium state it is approximately 30 liters.

    Metabolism

    Ν-detylation catalyzed by isoenzymes CYPlAl, 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 riotsiguata), which is further metabolized into pharmacologically inactive N- glucuronide.

    Isozyme CYPlAl 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 (see section "Special instructions").

    Excretion

    All riotsiguat (initial drug and metabolites) is excreted by the kidneys (33- 45 %) and through the intestine (48-59 %). From 4 before 19 % of the administered dose is excreted unchanged by the kidneys, approximately 9-44 % through the intestine.

    Based on the data in vitro determined that riotsiguat and its main metabolite are substrates for transport proteins P-gp (P-glycoprotein) and BCRP (protein resistance of breast cancer). Riotsiguat is a preparation with low clearance (systemic clearance is approximately 3-6 l / min). The half-life is approximately 7 hours in healthy volunteers and about 12 hours in patients.

    Pharmacokinetics in different patient groups

    Elderly patients

    In elderly patients (65 years and older) there was a higher concentration of riotsiguata in blood plasma than in young people, while AUC were about 40 % higher in the elderly, mainly due to an apparent decrease in total and renal clearance (see section "Method of administration and dose").

    Patients with impaired hepatic function

    In patients with cirrhosis of the liver, accompanied by a mild degree of 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 cirrhosis accompanied by moderate hepatic impairment (7-9 points on the Child-Pugh scale, class B), average AUC riotsiguata increased by 50-70 % in comparison with healthy volunteers from the control group (see section "Method of administration and dose").

    The use of riotsiguata in patients with severe hepatic impairment (10-15 points on the Child-Pugh scale, class C) is contraindicated because there are no clinical data for such patients (see section "Contraindications").

    Patients with impaired renal function

    In patients with renal failure compared with patients with normal renal function, the average values ​​of 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 creatinine clearance 80-50 ml / min, 49-30 ml / min and less 30 ml / min concentration of riotsiguata in blood plasma (AUC) increased by 43 %, 104 % or 44 %, respectively (see section "Method of administration and dose").

    No data for patients with creatinine clearance less than 15 ml / min or on hemodialysis.Therefore, the use of the drug is contraindicated in patients with creatinine clearance less than 15 ml / min or on hemodialysis (see section "Contraindications").

    Because the riotsiguat has a high degree of binding to blood plasma proteins, the possibility of removing it with dialysis is unlikely.

    Sex, ethnicity, body weight

    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 recurrent CTEPH after surgical treatment;

    - pulmonary arterial hypertension (PAH), group 1 according to WHO classification, II - III FK by WHO classification (in monotherapy or in combination with endothelin receptor antagonists or prostanoids):

    - idiopathic PAH,

    - hereditary PAH,

    - LAS, associated with connective tissue diseases.
    Contraindications:

    - increased sensitivity to riotsiguatu or any other component included in the preparation;

    - pregnancy and the period of breastfeeding (cm.section "Application during pregnancy and during breast-feeding");

    - age to 18 years;

    - simultaneous reception with nitrates or donators of nitric oxide (such as amyl nitrite) in any dosage form (see the section "Interaction with other medicinal products and other forms of interaction");

    - simultaneous use with the drugs of the group of phosphodiesterase inhibitors (PDE), including with drugs of the group of PDE-5 inhibitors, such as sildenafil, vardenafil, tadalafil, or with preparations of a group of nonspecific PDE inhibitors, such as dipyridamole and theophylline;

    - congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose in the composition);

    - severe dysfunction of the liver (more 9 points on the Child-Pugh scale, class C, clinical experience is not available);

    - severe arterial hypotension at the time of initiation of therapy (systolic blood pressure less than 95 mm Hg. Art., experience of clinical use is absent);

    - severe renal dysfunction (creatinine clearance less than 15 mL / min) and use in patients on hemodialysis (clinical experience is not available).

    Carefully:

    It is necessary to take extra care when prescribing the drug in the following situations:

    - in patients with pulmonary hypertension who have additional risk factors for bleeding from the respiratory tract, especially those who receive anticoagulant therapy (see section "Special instructions");

    - in patients receiving antihypertensive therapy or having initial arterial hypotension, hypovolemia, or severe obstruction of outflow from the left ventricle or autonomic dysfunction (see section "Special instructions");

    - when used simultaneously with strong inhibitors of the CYPlAI isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and strong inhibitors of P-gp / BCRP, such as an immunosuppressive drug ciclosporin A (see "Interaction with other drugs and other forms of interaction") - in patients with impaired renal function (creatinine clearance less than 80 ml / min, but more than 15 ml / min);

    - in patients with moderate impaired hepatic function (7-9 points on the Child-Pugh scale, class B);
    - in elderly patients (65 years and older).
    Pregnancy and lactation:

    Fertility

    There have been no special studies using riotsiguata to assess its effect on human fertility.

    During the treatment with Adempas, women of reproductive age should use effective methods of contraception.

    Pregnancy

    Adrenal is contraindicated in pregnancy.

    Breastfeeding period

    Adempas should not be used by women during breastfeeding because of the potential for serious adverse reactions in children who are breastfeeding. The decision to stop breastfeeding or to abolish and / or abstain from taking the drug during lactation should be taken in consideration of the risk-benefit ratio.

    Teratogenicity and embryotoxicity

    In studies on rats there was no effect on male and female fertility. The study of embryotoxicity in the models of rats and rabbits demonstrated the reproductive toxicity of riotsiguata. In a study in rats, there was an increased risk of heart disease, as well as a decrease in the frequency of pregnancy due to early fetal resorption with a systemic effect on the mother's body, which is approximately 7 times exceeded human exposure (2,5 mg 3 times a day). In a study on rabbits, starting with a level of systemic exposure that exceeds human exposure in 3 times (2,5 mg 3 once a day), miscarriages and embryotoxicity were observed.

    Dosing and Administration:

    For oral administration.

    The drug Adempas may be taken concurrently with a meal or regardless of the time of ingestion.

    Initiation of therapy: the recommended initial dose is 1,0 mg 3 once a day for 2 weeks. Tablets should be taken three times a day at intervals of approximately 6-8 hours, at the same time with food intake or regardless of the time of meal.

    If the systolic blood pressure is 95 mm Hg. Art. and above, and the patient thus does not have symptoms of arterial hypotension, dose should be increased by 0,5 mg every 2 weeks to the maximum daily dose 2,5 mg 3 times a day.

    If systolic blood pressure is less than 95 mm Hg. Art. dosage should be left as before, what the patient does not have symptoms of arterial hypotension.

    If, at any time during the titration phase, the systolic blood pressure is less than 95 mm Hg. Art.and the patient thus has signs of arterial hypotension, the current single dose should be reduced by 0,5 mg, that is, recommend the appointment of a previously accepted and well tolerated dose.

    Maintenance dose

    A selected individual 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, it can be reduced at any time of treatment.

    Cancellation treatment

    If necessary, a break in treatment for 3 day or more, it is necessary to return to the initial dose and resume taking the drug, starting with the dose 1 mg 3 once a day for 2 weeks; continue treatment with subsequent titration of the dose, as described above.

    Special patient groups

    Children

    The safety and efficacy of Adempas has not been studied in patients younger 18 years. Since there are no available data on the use of Adempas in children, it is contraindicated in patients before 18 years (see the section "Contraindications").

    Elderly patients

    The elderly (65 years and older) patients should be especially careful, including when choosing a dose.

    Patients with impaired renal function

    In patients with impaired renal function (creatinine clearance less than 80 ml / min, but more 15 ml / min), the more pronounced effect of 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 impairment of kidney function (creatinine clearance less than 15 ml / min) or on hemodialysis because no studies have been conducted in these patients (see section "Contraindications").

    Patients with impaired hepatic function

    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 impaired hepatic function (7-9 points on the Child-Pugh scale, class B), a stronger effect of Adempas (see section "Pharmacokinetics"). When choosing a dose in these patients should be very careful.

    The use of Adempas in patients with severe liver dysfunction (more 9 points on the Child-Pugh scale, class C) is contraindicated, since studies in such patients have not been conducted (see section "Contraindications").

    Tobacco smoking

    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. A dose adjustment may be required if the patient begins or stops smoking during the treatment with Adempas (see section "Special instructions").

    Side effects:

    The adverse events presented below are listed according to the frequency of occurrence in clinical trials. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10000 and <1/1000), rarely (< 1/10000).

    Infectious and parasitic diseases

    Often: gastroenteritis.

    Violations of the blood and lymphatic system

    Often: anemia (including relevant laboratory indicators).

    Disturbances from the nervous system

    Often: dizziness, headache.

    Violations from the heart and blood vessels

    Often: heart palpitations, lowering of blood pressure.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: hemoptysis, nosebleed, nasal congestion.

    Infrequently: pulmonary hemorrhage.

    Disturbances from the gastrointestinal tract (GIT)

    Often: dyspepsia, diarrhea, nausea, vomiting.

    Often: gastritis, gastroesophageal reflux disease, dysphagia, pain in different parts of the digestive tract, constipation, bloating.

    General disorders and disorders at the site of administration

    Often: peripheral edema.

    * a case of fatal pulmonary hemorrhage was reported as part of a long-term study without a control group.

    Overdose:

    Symptoms

    An unintentional overdose of 9-25 mg of riotsiguata was reported within 2-32 days. Undesirable reactions were similar to those observed with lower doses (see the "Side effect" section).

    Treatment

    The specific antidote is unknown. In the case of an overdose, standard support measures should be used in accordance with clinical need.With the development of a marked decrease in blood pressure, active hemodynamic support may be required. Because the riotsiguat has a high degree of binding to blood plasma proteins, the possibility of removing it with dialysis is unlikely.

    Interaction:Pharmacokinetic interactions
    Rioziguat is derived mainly through oxidative metabolism, mediated by the cytochrome P450 isoenzyme system (isozymes CYPlAl, CYP3A4, CYP2C8, CYP2J2), and also unchanged through the intestine or kidneys during glomerular filtration.
    Based on in vitro studies, it was found that riotsiguat is a substrate for the 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 effectiveness of riotsiguata.
    In vitro it was shown that ketoconazole, classified as a potent inhibitor of the isoenzyme CYP3A4 and P-gp, is an inhibitor of multiple metabolic pathways involving the cytochrome and P-gp / BCRP isoenzyme system involved in the metabolism and excretion of riotsiguata.Simultaneous use of ketoconazole 400 mg once a day resulted in an increase of 150% (range up to 370%) in the average AUC of the rhyocyclate and an increase in Cmax by 46%. The final half-life increased from 7.3 to 9.2 hours, and the total clearance of riotsiguata decreased from 6.1 to 2.4 l / h.
    Thus, the simultaneous use of Adempas with strong inhibitors of multiple metabolic pathways involving cytochrome and P-gp / BCRP isoenzymes, such as azole antifungal agents (for example, ketoconazole, itraconazole) or HIV protease inhibitors (e.g., ritonavir) (see section "Special instructions").
    Drugs that strongly inhibit P-gp / BCRP, such as an immunosuppressant ciclosporin A, should be used with caution (see section "Special instructions").
    Of the recombinant cytochrome isoenzymes studied in vitro, the isoenzyme CYPlAl most effectively catalyzed the formation of the main metabolite of riotsiguata. Preparations of the class of tyrosine kinase inhibitors are potent inhibitors of the CYPlAl isoenzyme, in this case erlotinib and gefitinib exhibited the greatest inhibitory activity in vitro. Thus, simultaneous use with drugs that are inhibitors of the isoenzyme CYPlAl can lead to an increased effect of riotsiguata, especially in smokers.Therefore, strong inhibitors of the CYPlAl isoenzyme should be used with caution (see section "Special instructions").
    The simultaneous use of clarithromycin (500 mg twice daily), attributed to the strong inhibitors of the isoenzyme CYP3A4, also a P-gp inhibitor, moderately increased the average AUC of the riotsiguata by 41% without significant change in Cmax. Such changes are clinically insignificant.
    The simultaneous use of drugs that increase the pH of the gastrointestinal tract can lead to a lower bioavailability when taken orally, since the solubility of riotsiguata is reduced at a neutral pH compared to an acidic medium.
    The appointment of omeprazole proton pump inhibitor (40 mg once daily) with riotsiguate reduces the mean AUC of riotsiguata by 26%, and the mean Cmax by 35%. These changes are clinically insignificant.
    Antacids should be taken at least an hour after taking riotsiguata, because simultaneous use of antacids based on aluminum hydroxide and / or magnesium hydroxide reduces the average AUC of the rhyocyclate by 34%, and the average Cmax by 56%.
    Bosentan, which is a moderate inhibitor of the CYP3A4 isoenzyme, causes a decrease in the equilibrium concentration of riotsiguata in plasma in patients with PAH by 27%, without affecting the efficacy of the combination.
    Simultaneous use of riotsiguata and strong inducers of the CYP3A4 isoenzyme (eg, phenytoin, carbamazepine, phenobarbital or preparations containing St. John's wort) can also lead to a decrease in the concentration of riotsiguata in the blood plasma.
    The effect of riotsiguata on other substances
    Rioziguat and its main metabolite are neither inhibitors nor inducers of the main cytochrome isoenzymes (including the CYP3A4 isoenzyme) or transport proteins (eg, P-gp / BCRP) at therapeutic concentrations under conditions in vitro.
    The lack of pharmacokinetic interactions between the riotsiguate and the marker substrate of the CYP3A4 isozyme with midazolam has been demonstrated in vivo.
    It was found that in vitro riotsiguat and its main metabolite are potent inhibitors of the CYPlAl isoenzyme. Thus, it is not possible to exclude clinically significant drug interactions with concomitantly taken drugs, which are largely excreted by metabolism mediated by the CYPlAl isoenzyme, such as erlotinib or granisetron.
    Pharmacodynamic interactions
    Nitrates
    The simultaneous use of riotsiguata and nitrates or donators of nitric oxide (such as amyl nitrite) in any dosage form is contraindicated, since with the use of riotsiguata in a dosage of 2.5 mg in the form of film-coated tablets, the antihypertensive effect of nitroglycerin (0.4 mg, under the tongue) increased 4 and 8 hours after taking riotsiguata (see Fig. section "Contraindications").
    PDE-5 Inhibitors
    In animal studies, a reduction in systemic arterial pressure was shown in the combination of riotsiguata with sildenafil or vardenafil. With the use of increased doses, in a number of cases an additional decrease in systemic blood pressure was observed.
    In the extrapolation study of drug interactions involving 7 patients with PAH who received continuous treatment with sildenafil (20 mg 3 times a day), a single dose of riotsiguata (0.5 mg and 1 mg sequentially) led to a summation of the effects of drugs on hemodynamics. Doses of riotsiguata over 1.0 mg in this study have not been studied.
    A 12-week study of a combination of a stable dose of sildenafil (20 mg 3 r / day) and riotsiguata (1.0-2.5 mg 3 r / day) versus sildenafil monotherapy in 18 patients with PAH was performed.In the extended phase of the study (in the absence of a control group), concomitant use of sildenafil and riotsiguata resulted in a higher frequency of riotsiguata cancellation, mainly as a result of arterial hypotension. There was no evidence of a favorable clinical effect of this combination in the study population. Simultaneous reception of riotsiguata and inhibitors of PDE-5 (such as sildenafil, tadalafil, vardenafil) is contraindicated (see the section "Contraindications").
    Warfarin
    Simultaneous treatment with riotsiguatom and warfarin did not affect prothrombin time. It is assumed that the simultaneous use of riotsiguata with other coumarin derivatives also will not affect prothrombin time.
    The lack of pharmacokinetic interactions between riotsiguate and the substrate of the CYP2C9 isoenzyme warfarin was demonstrated under conditions in vivo.
    Acetylsalicylic acid
    Rioziguat did not cause an increase in the time of bleeding caused by the use of acetylsalicylic acid as an antiplatelet agent, and also did not affect the aggregation of platelets in humans.
    Special instructions:Venousocclusion disease of the lungs
    The use of Adempas in patients with veno-occlusive disease of the lung (VOBL) is not recommended, since pulmonary vasodilators can significantly worsen the clinical state of such patients. When symptoms of pulmonary edema appear, one should think about the possibility of developing an associated VOBL, treatment with Adempas should then be discontinued.
    Bleeding from the respiratory tract
    In patients with pulmonary hypertension, there is an increased chance of bleeding from the respiratory tract, especially among patients receiving anticoagulant therapy.
    When treated with Adempas, the risk of serious and / or fatal bleeding from the respiratory tract may increase, especially in the presence of risk factors, such as the recent episode of severe hemoptysis, including his treatment with bronchial arterial embolization. The doctor prescribing the drug should regularly assess the risk-benefit ratio for each individual patient.
    Vasodilator effect
    The drug Adempas has vasodilating properties, which can lead to a decrease in blood pressure.Before the appointment of the drug, the doctor should carefully evaluate the risk of developing unwanted vasodilator effects in patients with specific concomitant diseases (eg, in patients receiving antihypertensive therapy or with initial arterial hypotension, hypovolemia, severe obstruction of left ventricular outflow pathways, or autonomic dysfunction).
    Combined use with other medicinal products
    Simultaneous application of Adempas preparation with potent inhibitors of cytochrome and P-gp / BCRP isoenzymes, such as azole antifungal agents (for example, ketoconazole, itraconazole) or HIV protease inhibitors (e.g., ritonavir), is not recommended due to the pronounced strengthening of the action of the drug Adempas (see the section "Interaction with other medicinal products and other forms of interaction").
    Simultaneous use of Adempas with strong inhibitors of the CYPlAl isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and strong inhibitors of P-gp / BCRP, such as an immunosuppressant ciclosporin A, can strengthen the action of the drug Adempas (see.section "Interaction with other medicinal products and other forms of interaction"). These drugs should be used with caution. It is necessary to control blood pressure and consider the possibility of reducing the dose of the drug Adempas.
    Populations of patients, studies in which were not conducted
    Adempas has not been studied in the following groups of patients, and therefore its use is contraindicated:
    - Patients with systolic blood pressure less than 95 mm Hg. Art. at the time of treatment initiation;
    - Patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale, grade C);
    - Patients with severe impairment of renal function (creatinine clearance less than 15 ml / min) or who are on hemodialysis.
    Information for individual patient groups
    In smokers, the effect of riotsiguata is reduced by 50-60% (see the section "Pharmacokinetic properties"). Such patients are strongly advised to quit smoking.
    Effect on the ability to drive transp. cf. and fur:There have been reports of dizziness in some patients (see the "Side effect" section), so care should be taken when driving vehicles and when working with other mechanisms.
    Form release / dosage:Film-coated tablets, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg.
    Packaging:For 21 tablets in a foil blister of aluminum and polypropylene, 2 or 4 blisters with instructions for use are placed in a cardboard box.
    Storage conditions:Store at a temperature not exceeding 30 ° C.
    Keep out of the reach of children.
    Shelf life:3 years.
    Do not use after the expiration date stated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002639
    Date of registration:25.09.2014
    Expiration Date:25.09.2019
    The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany
    Manufacturer: & nbsp
    Representation: & nbspBAYER, AOBAYER, AO
    Information update date: & nbsp04.02.2017
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