trenbolone hexahydrobenzylcarbonate

Adempas / Adempas.

International nonproprietary name:

Riotsiguat / Riociguat.

Dosage Form:

trenbolone hexahydrobenzylcarbonate film-coated.

Composition

A film-coated tablet 0.5 mg contains: Active ingredient: riotsiguat micronized 0.50 mg. Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone;Hypromellose 2910, 3.00 mg; 39.80 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.10 mg sodium lauryl sulfate; film coating: 1.10 mg giproloza hypromellose-2910 0.36 mg 0.21 mg propylene glycol, titanium dioxide 0.83 mg. A film-coated tablet 1.0 mg contains: Active ingredient: riotsiguat micronized 1.00 mg. Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 39.20 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.82 mg of titanium dioxide, yellow iron oxide coloring agent 0.01 mg One tablet is coated with film coating contains 1.5 mg : Active ingredient: riotsiguat micronized 1.50 mg.Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 38.70 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.73 mg of titanium dioxide, yellow iron oxide coloring agent 0.10 mg One tablet is coated with film coating contains 2.0 mg : Active ingredient: riotsiguat micronized 2.00 mg. Excipients:microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 38.20 mg lactose monohydrate; 0.60 mg of magnesium stearate;0.20 mg sodium lauryl sulfate; film coating:. giproloza 1.10 mg Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.61 mg of titanium dioxide, yellow iron oxide coloring agent 0.20 mg iron oxide red dye 0.02 mg One tablet film-coated trenbolone hexahydrobenzylcarbonate, 2.5 mg contains: Active ingredient: riotsiguat micronized 2.50 mg.Excipients: microcrystalline cellulose 35.00 mg; 6.00 mg of crospovidone; Hypromellose 2910, 3.00 mg; 37.70 mg lactose monohydrate; 0.60 mg of magnesium stearate; 0.20 mg sodium lauryl sulfate; film coating: 1.10 mg giproloza, Hypromellose 2910, 0.36 mg, 0.21 mg of propylene glycol, 0.35 mg of titanium dioxide, yellow iron oxide coloring agent 0.40 mg iron oxide red dye 0.08 mg.

Description

Film-coated trenbolone hexahydrobenzylcarbonate, 0.5 mg: Round biconvex trenbolone hexahydrobenzylcarbonate film-coated, white, one side coated by extrusion «R» and “0.5” on the other side of the Bayer company logo in the form of a cross. The trenbolone hexahydrobenzylcarbonate film-coated 1 0 mg: round biconvex trenbolone hexahydrobenzylcarbonate film-coated, pale yellow in color on one side by extrusion coated «R1», on the other side of the Bayer company logo of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 1.5 mg: round biconvex trenbolone hexahydrobenzylcarbonate coated film-coated, yellow. on one side by extrusion coated «R» and “1.5” on the other side of the Bayer company logo in the form of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 2.0 mg: Round biconvex trenbolone hexahydrobenzylcarbonate film-coated, pale orange, on one side by extrusion coated «R2», on the other side of the Bayer company logo of a cross. trenbolone hexahydrobenzylcarbonate are film-coated, 2.5 mg: round biconvex trenbolone hexahydrobenzylcarbonate film-coated, brownish-orange, on one side by extrusion coated «R» and «2.5 “on the other side of the Bayer company logo in the shape of a cross.

Pharmacotherapeutic group

Antihypertensives – guanylate cyclase stimulant.

ATX code : C02KX05.

pharmacological properties

Pharmacodynamics The mechanism of action Riotsiguat is a stimulator of soluble guanylate cyclase (sGC), the enzyme cardiopulmonary receptor and nitrogen oxide (N0). By binding to N0 sGC enzyme catalyzes the synthesis of the signaling molecule of cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in the regulation of influencing vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, disturbance of nitric oxide synthesis and lack of stimulation pathway sGC-NO-cGMP. Riotsiguat has a dual mechanism of action. It sensitizes to cGMP by endogenous NO stabilizing connection NO-cGMP. Riotsiguat also directly stimulating sGC through another communication station, regardless of N0. Riotsiguat restores the metabolic pathway of NO-sGC-cGMP and causes an increase in cGMP production. Efficacy in patients with chronic thromboembolic pulmonary hypertension (CTEPH) Efficacy was evaluated in a randomized, double-blind, international, multicenter, placebo -controlled phase III study (CHEST-1), which included inoperable patients or patients with persistent and / or recurrent CTEPH after pulmonary endarterectomy performed (group 4, according to the classification of the World health organization, WHO). The study included 261 patients with varying degrees of severity of the disease (functional class FC), of which 31% of patients assigned to functional class II according to the WHO classification (FC I WHO), 64% – FC III WHO, with the average distance in the test 6 . -minutnoy walk (6MHT, 150 – 450 m) 347 m Primary efficacy endpoint: change in distance 6MHT to week 16 from baseline during the treatment of the results achieved:

 

  • a change in the distance 6MHT to week 16 in the group riotsiguata 46 m compared with placebo (p <0.0001);
  • a significant reduction in pulmonary vascular resistance (PVR), p <0.0001, the placebo-corrected mean change from baseline to -246 dyn × × 5 cm; 95% confidence interval (CI) of -303 to -190; p <0.0001;significant reduction in N-terminal fragment of brain natriuretic peptide (NT-proBNP), the placebo corrected mean change from baseline -444 ng / l CI -843 to -45 riotsiguata group compared to placebo;
  • significant improvement in at least one of FC 16 week riotsiguata group in 33% of patients in the placebo group – 15%; reduction of at least one FC in 5% of patients in riotsiguata group, 7% in the placebo group (p = 0.0026). FC unchanged in 62% of patients riotsiguata group, 78% – in the placebo group.
    An improvement in hemodynamic parameters riotsiguata group compared to placebo: statistically significant reduction in PVR, secondary pulmonary artery pressure (mean PAP) (minus 5.0 mm Hg. Article, p <0.0001) and an increase in cardiac index (CI) of 0.47 l / min / m2.; (p <0.0001). Long-term treatment HGELG (CHEST-2) consisted of 237 patients who completed the study CHEST-1. The average duration of treatment at the time of data cut-off – 388 days. The CHEST-2 study, further improvements were observed from a distance 6MHT FC. One-year survival rate – 98%. Efficacy in patients with pulmonary arterial hypertension (PAH) The efficacy was evaluated in a randomized, double-blind, international, multicenter, placebo-controlled phase III study (PATENT-1), in which 443 patients participated (baseline clinical status: 42% FC II of, 54% of FC III WHO classification, the average distance in 6MHT (150 – 450 m), 363 m), untreated or treated with an endothelin receptor antagonist (ERA) or an analogue of prostacyclin (AP) (inhalation, orally or subcutaneously ). The population of patients included men and women aged 18 to 80 years; 61% – idiopathic PAH, 2% – hereditary PAH, 25% – PAH associated with connective tissue disease, 8% – PAH associated with congenital heart disease, 3% – PAH associated with portal hypertension, 1% – PAH associated . with reception anorectics or amphetamine (group 1 according to the WHO classification) Primary efficacy endpoint: change in distance 6MHT to 12 weeks during the treatment of the results achieved:
  • 6.MHT change the distance to 12 week group riotsiguata 36 m compared with placebo (p <0.0001);
  • significant reduction in PVR p <0.0001 placebo corrected mean change from baseline to -226 dyne × × 5 cm; 95% CI, -281 to -170; p <0.0001;
  • a significant decrease in NT-proBNP placebo-corrected mean change from baseline -432 ng / L, 95% CI -782 to -82 in the group riotsiguata compared with placebo;
  • significant improvement in at least one group riotsiguata FC in 21% of patients in the placebo group – 14%;
  • the delay clinical worsening over time was observed in riotsiguata group (p = 0.0046; stratified log-rank test);
  • Clinical manifestations of significantly less deteriorating to 12 week riotsiguata group (1.2%) compared with placebo (6.3%) (p = 0.0285, Mantel-Haenszel test);
  • dyspnea rating on a scale of Borg: significant improvement (for riotsiguata -0.4 compared to 0.1 for placebo; p = 0.0022).
    An improvement in hemodynamic parameters riotsiguata group compared to placebo: PASP (minus 3.8 mmHg, p <0.0001) and an increase in the SI (0.56 l / min / m2. p <0.0001) Long-term treatment of PAH (PATENT-2) included 363 patients who completed the study PATENT- 1. Average: The duration of treatment at the time of data cut-off – 438 days. In PATENT-2 study, further improvements were observed from a distance 6MHT FC. One-year survival rate – 96%.

    Pharmacokinetics Absorption The absolute bioavailability of riotsiguata high (94%). Riotsiguat rapidly absorbed, the maximum plasma concentration (C max ) is achieved through 1-1.5 hours after ingestion.Riotsiguata absorption occurs throughout the gastro-intestinal tract (GIT), preferably in the upper part. In the distal parts of the gastrointestinal tract absorption is reduced. Use of the drug simultaneously with the meal did not affect the value of the area under the curve “concentration-time» (AUC) riotsiguata, C max was reduced to the minimum limit (35% reduction). This change is considered to be clinically significant. Distribution Relationship with the blood supply is high and is approximately 95%. The main binding components are bovine serum albumin and alpha-1-acid glycoprotein. The volume of distribution is an average, while in the equilibrium state, it is approximately 30 liters. Metabolism N-demethylation, catalyzed isozymes CYP1A1, CYP3A4, CYP2C8 and CYP2J2 It is the main route of metabolism riotsiguata, leading to the formation of its major circulating metabolite (pharmacological activity: from 1/10 to 1/3 riotsiguata)., which is further metabolized to the pharmacologically inactive N-glucuronideisozyme CYP1A1 catalyze the formation of the major metabolite in the liver and riotsiguata light. This process is enhanced by polycyclic aromatic hydrocarbons, for example, contained in the smoke from cigarettes (see. Section “Special Instructions”). Removing All riotsiguat (parent drug and metabolites) excreted by the kidneys (33-45%) and through the gut (48-59%) . From 4 to 19% of the administered dose excreted unchanged by the kidneys, approximately 9-44% -through the intestine. In in vitro data basis it established that riotsiguat and its major metabolite are substrates for the transporter proteins P-gp (P-glycoprotein) and BCRP (protein resistant breast cancer). Riotsiguat is a drug with low clearance (systemic clearance is approximately 6.3 L / min). The half-life of about 7 hours in healthy volunteers and about 12 hours in patients.

    Pharmacokinetics in different patient populations Elderly patients In elderly patients (65 years and older) had higher concentrations riotsiguata in blood plasma than the young, and the indicators AUC were approximately 40% higher in the elderly, mainly due to the apparent reduction in the total and renal clearance (see. section “dosage and administration”). patients with hepatic impairment In patients with cirrhosis of the liver, accompanied by mild hepatic insufficiency (5-6 points on a scale Child-Pugh class a) were observed clinically significant changes of the drug. in patients with cirrhosis of the liver, accompanied by moderate hepatic insufficiency (7-9 points on a scale Child-Pugh class B), the mean AUC riotsiguata increased by 50-70% in comparison with healthy volunteers from the control group (see. section ” dosage and administration “). application riotsiguata patients with severe hepatic insufficiency (10-15 points on a scale Child-Pugh class C) is contraindicated, since clinical data for these patients are missing (see. See “Contraindications”). Patients with renal impairment In patients with renal impairment compared with patients with normal renal function, the mean values ​​normalized for dose and riotsiguata action intensity were higher. The corresponding figures for the major metabolite were higher in patients with renal insufficiency compared with healthy volunteers. In patients with a creatinine clearance of 80-50 ml / min, 49-30 ml / min and less than 30 ml / min riotsiguata plasma concentration (AUC) increased by 43%, 44% or 104%, respectively (see., “Method section dosage and administration “). No data for patients with a creatinine clearance less than 15 mL / min or hemodialysis. Consequently, the use of the drug is contraindicated in patients with creatinine clearance less than 15 ml / min or on hemodialysis (see. Section “Contraindications”). Since riotsiguat has a high degree of binding to plasma proteins, the possibility of removing it using dialysis is unlikely. Paul, ethnicity, body weight There were no significant differences riotsiguata effectiveness based on gender, ethnic group or patient body weight.

    Indications

     

    • Chronic thromboembolic pulmonary hypertension (CTEPH), a group of 4 on the WHO classification:
      • inoperable CTEPH,
      • persistent or recurrent CTEPH after surgery;
    • pulmonary arterial hypertension (PAH), a group 1 according to the WHO classification, II – III FC according to the WHO classification (as monotherapy or in combination with an endothelin receptor antagonist or prostanoids):
      • idiopathic PAH
      • heritable PAH,
      • PAH associated with connective tissue diseases.

    Contraindications

     

    • Hypersensitivity to riotsiguatu or any other components of the drug;
    • Pregnancy and breast-feeding (see “Pregnancy and breastfeeding period” section.)
    • age of 18 years;
    • Simultaneous reception with nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form (see “Interaction with other medicinal products and other forms of interaction” section).
    • simultaneous application of drugs group phosphodiesterase inhibitors (PDE), including drugs with a group of PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, or a group of nonspecific drugs PDE inhibitors such as dipyridamole and theophylline;
    • congenital deficiency of lactase, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose);
    • severe liver function abnormalities (more than 9 points on a scale Child-Pugh Class C, clinical application experience is absent);
    • severe hypotension at the start of therapy (systolic blood pressure less than 95 mm Hg, clinical application experience is missing..);
    • severe renal dysfunction (creatinine clearance less than 15 ml / min), and the use of in patients on hemodialysis (clinical application experience is absent).

    Carefully

    Observe extra caution when administering the drug 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 anticoagulation therapy (see “Special Instructions” section.)
  • in patients receiving antihypertensive therapy or with an initial hypotension, hypovolemia, or severe obstruction of the outflow tract of the left ventricle, or autonomic dysfunction (see “Special Instructions” section.)
  • while the use of potent inhibitors of CYP1A1 isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as an immunosuppressive drug cyclosporin A (see “Interaction with other medicinal products and other forms of interaction” section).
  • 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).

    Application of pregnancy and during breastfeeding

    Fertility
    is not conducted specific studies with riotsiguata to assess its impact on fertility in humans.
    During treatment with Adempas women of childbearing age should use effective methods of contraception. Pregnancy In pregnancy, drug Adempas contraindicated. Breastfeeding Period drug Adempas should not be used in women during breast breastfeeding because of the potential for serious adverse reactions in children who are breastfed. The decision on the termination of breastfeeding or the cancellation and / or abstinence during lactation should be made ​​taking into account the evaluation of the risk-benefit ratio. Teratogenicity and embryotoxicity were observed effects on male and female fertility in studies on rats. Study on the models of embryotoxicity in rats and rabbits showed reproductive toxicity riotsiguata. In a study on rats there was an increased risk of heart disease, as well as reducing the frequency of pregnancy in an early fetal resorption in systemic exposure to the mother’s body, which is about 7 times larger than the effect in humans (2.5 mg 3 times per day ). In a study in rabbits since systemic exposure levels exceeding the human exposure to 3-fold (2.5 mg three times a day), miscarriages and embryotoxicity was observed.

    Dosing and Administration

    . For oral
    drug Adempas may be taken together with a meal or independently of meal times. Initiation of therapy: The recommended starting dose is 1.0 mg 3 times a day for 2 weeks. The trenbolone hexahydrobenzylcarbonate should be taken three times a day at intervals of about 6-8 hours, together with a meal or independently of meal times. If the systolic blood pressure of 95 mm Hg. Art. above and in a patient with no signs of hypotension observed,the dose should be increased by 0.5 mg every 2 weeks up to a maximum daily dose of 2.5 mg three times a day. If the systolic blood pressure less than 95 mmHg. v., the dosage should be kept the same, provided that the patient has marked symptoms of hypotension . If at any point on the titration phase systolic blood pressure less than 95 mmHg. Art. and a patient with signs of arterial hypotension, the current single dose should be reduced by 0.5 mg, that is, recommend the appointment of the previously received and well tolerated dose. The maintenance dose selected individual dose should be maintained, unless the symptoms of hypotension develop. Maximum Adempas daily dose of the drug is 7.5 mg. In the case of missing the next dose should be taken the next dose according to the specific application of the scheme. In the case of adverse reactions after applying the prescribed dose of the drug, it can be reduced at any time during treatment. Cancel treatment If necessary, the suspension of the treatment for 3 days and more, you must return to the initial dose and resume taking the drug, starting with a dose of 1 mg 3 times a day for 2 weeks; continue treatment followed by titration as described above.

    Special patient groups Children Safety and efficacy Adempas the drug has not been studied in patients younger than 18 years. Since the available data on the use of the drug Adempas in children are not available, it is contraindicated in patients under 18 years of age (see. “Contraindications”). Elderly patients Elderly (65 years and older) patients should be treated very carefully, including the selection of doses . patients with impaired renal function in patients with impaired renal function (creatinine clearance less than 80 mL / min, but more than 15 ml / min) had a more pronounced effect Adempas drug, so you should be very careful in the selection of dose in these patients. Do not use this medication Adempas in patients with severely impaired renal function (creatinine clearance less than 15 mL / min) or on dialysis, because research in these patients have not been conducted (see. section “Contraindications”). patients with hepatic impairment concentrations riotsiguata in the blood plasma of patients with a slight 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 ) noted a dramatic effect Adempas drug (see. “Pharmacokinetics” section). In the selection of doses should be particularly careful in these patients. Use of the drug Adempas in patients with severe hepatic impairment (more than 9 points on a scale Child-Pugh class C) is contraindicated, since studies in these patients have not been conducted (see. Section “Contraindications “).tobacco smoking patients are strongly encouraged to give up smoking because riotsiguata concentration in blood plasma in smokers is substantially reduced in comparison with non-smokers. You may need dose adjustment in case the patient starts or stops smoking during treatment with Adempas (see. “Special Instructions” section).

    Side effect

    Adverse events reported below are listed according to frequency of occurrence in clinical studies. The frequency is defined as follows: very common (≥ 1/10), often (≥ 1/100 and <1/10), uncommon (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), very rare (<1/10 000). Infectious and parasitic diseases often: gastroenteritis. Violations of the blood and lymphatic system Common:. anemia (including relevant laboratory parameters) disorders of the nervous system very common: dizziness, headache. Violations of the heart and blood vessels Common: palpitation, reduction in blood pressure. Violations of the respiratory system, organs, thoracic and mediastinal disorders Common: hemoptysis, epistaxis, nasal congestion. Uncommon: pulmonary hemorrhage. * on the part of Violations gastrointestinal (GI) tractVery common: dyspepsia, diarrhea, nausea, vomiting. Often: gastritis, gastroesophageal reflux disease, dysphagia, pain in different parts of the gastrointestinal tract, constipation, bloating. General disorders and injection site Very common:. Peripheral edema * reported case of fatal pulmonary bleeding within the framework of long-term studies with no control group.

    Overdose

    Symptoms
    reported unintentional overdose 9-25 mg riotsiguata within 2-32 days. Adverse reactions were similar to those observed when taking lower doses (see. Section “Side effects”). Treatment of specific antidote is not known. In case of overdose should apply the standard supportive measures, in accordance with the clinical need. Active hemodynamic support may be required for the development of significant decrease in blood pressure . As riotsiguat has a high degree of binding to plasma proteins, the possibility of removing it using dialysis is unlikely.

    Interaction with other drugs and other forms of interaction

    Pharmacokinetic interactions
    Riotsiguat derived primarily through oxidative metabolism mediated by the system of cytochrome P450 isoenzymes (isozymes CYP1A1, CYP3A4, CYP2C8, CYP2J2) , as well as unchanged through the intestines or kidneys during glomerular filtration.
    Found that riotsiguat in vitro studies based on It 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 of proteins may affect the efficiency riotsiguata.
    In vitro it was shown that ketoconazole is classified as a potent inhibitor of isozyme CYP3A4 and P-gp, is an inhibitor of multiple metabolic pathways involving isoenzymes of cytochrome and P-gp / BCRP, involved in the metabolism and excretion riotsiguata. The simultaneous use of ketoconazole at a dose of 400 mg once a day resulted in a 150% increase (to 370% range) and the average increase in AUC riotsiguata C max by 46%. The final half-life increased from 7.3 to 9.2 hours and total clearance riotsiguata decreased from 6.1 to 2.4 l / h.
    Therefore, not recommended the simultaneous use of the drug Adempas with potent inhibitors of multiple metabolic pathways involving cytochrome isoenzymes and P-gp / BCRP, such as azole antifungals (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (such as ritonavir) (cm. “special instructions” section).
    formulations strongly inhibit P-gp / BCRP, such as the immunosuppressant cyclosporin a should be used with caution (see. section “Special instructions”).
    from the recombinant isoenzymes of cytochrome studied in vitro, CYP1A1 isozyme more effectively catalyze the formation of the major metabolite riotsiguata. Class of tyrosine kinase inhibitor drugs are potent inhibitors of CYP1A1 isoenzyme, with erlotinib and gefitinib showed the highest inhibitory activity in vitro. Thus, the simultaneous use with drugs that are inhibitors of CYP1A1 isoenzyme may lead to increased riotsiguata effect, especially in smokers. Hence, strong inhibitors of CYP1A1 isoenzyme should be used with caution (see. “Special Instructions” section). Concomitant use of clarithromycin (500 mg 2 times a day), referred to the strong inhibitors of CYP3A4 isoenzyme, is also an inhibitor of P-gp, increased the mean AUC moderately riotsiguata 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 riotsiguata solubility decreases at a neutral pH compared with the acidic medium.
    Assignment before and during therapy riotsiguatom proton pump inhibitor omeprazole (40 mg once a day) reduces the average AUC riotsiguata 26%, and an average C max by 35%. These changes are clinically significant.
    Antacids should be taken at least one hour after receiving riotsiguata, since simultaneous use of antacids based on aluminum hydroxide and / or magnesium hydroxide reduces the average AUC riotsiguata 34%, and an average C max by 56%.
    Bosentan, which is a moderate inhibitor of isozyme CYP3A4, causes a decrease in the equilibrium riotsiguata plasma concentrations in patients with LAS 27% without impacting on the efficiency of the combination.
    Simultaneous use riotsiguata and strong inducers isoenzyme CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital or preparations containing St. John’s wort) may also reduce riotsiguata plasma concentrations. Effect riotsiguata other substances Riotsiguat and its major metabolite are neither inhibitors nor inductors major isoenzymes of cytochrome (including isozyme CYP3A4) or transport proteins (e.g., P-gp / BCRP) at therapeutic concentrations under conditions in vitro. The lack of pharmacokinetic interaction between the marker and substrate riotsiguatom isoenzyme CYP3A4 midazolam was demonstrated in vivo. it was found that in vitro riotsiguat and its major metabolite are potent inhibitors isoenzyme CYP1A1. Thus, we can not exclude a clinically significant drug-drug interactions with drugs taken at the same time, which are largely derived by metabolism mediated isoenzyme of CYP1A1, such as erlotinib or granisetron.

    Pharmacodynamic interactions Nitrates simultaneous use riotsiguata and nitrates or nitric oxide donators (such as amyl nitrite) in any dosage form is contraindicated because riotsiguata when applied at a dosage of 2.5 mg in trenbolone hexahydrobenzylcarbonate coated with a film coating were increased hypotensive effect of nitroglycerin (0.4 mg, under the tongue), received after 4 and 8 hours after administration riotsiguata (see. section “Contraindications”). PDE5 inhibitors systemic blood pressure reduction has been demonstrated in animal studies, when combined riotsiguata with sildenafil or vardenafil. In the application of increased doses in some cases, there was an additional reduction in systemic blood pressure. In ekstropolyatsionnom study drug interactions with 7 patients with PAH receiving chronic treatment with sildenafil (20 mg 3 times a day), single dose riotsiguata (0.5 mg and 1 mg series) led to the summation of the effect of drugs on hemodynamics. Doses above 1.0 mg riotsiguata in this study have not been studied. 12-week study using a combination of a stable dose of sildenafil (20 mg 3 / day) and riotsiguata was conducted (at a dose of 1.0-2.5 mg 3 / day) compared with sildenafil monotherapy in 18 patients with PAH. In the extended phase of the study (in the absence of a control group), the simultaneous use of sildenafil and riotsiguata led to a higher frequency cancellation riotsiguata, mainly due to hypotension. There was no evidence of clinical benefit of this combination in the study population. Simultaneous reception riotsiguata and PDE-5 inhibitors (such as sildenafil, tadalafil, vardenafil) is contraindicated (see. “Contraindications”). Warfarin The simultaneous treatment riotsiguatom and warfarin did not affect the prothrombin time. It is assumed that the concurrent use riotsiguata other coumarin derivatives will also have no effect on prothrombin time. The lack of pharmacokinetic interaction between riotsiguatom and substrate isoenzyme CYP2C9 with warfarin has been demonstrated under in vivo. Acetylsalicylic acidRiotsiguat not cause prolonged bleeding time caused by taking aspirin an antiplatelet agent, and had no effect on platelet aggregation in humans.

    special instructions

    Venookklyuzionnaya lung disease
    Use of the drug in patients with Adempas venookklyuzionnoy pulmonary disease (roach) is not recommended, because the pulmonary vasodilators may significantly worsen the clinical condition of these patients. When symptoms of pulmonary edema should think about the possibility of associated roach, treatment with Adempas in this case should be dismissed. 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. When treating Adempas risk of serious drug and / or fatal bleeding from the respiratory tract may increase, particularly in the presence of risk factors such as the recent episode severe hemoptysis, including its treatment with bronchial arterial embolization. The physician prescribers should regularly assess the risk-benefit ratio in each individual patient. Vasodilating effect of drug Adempas has vasodilating properties, which may lead to lower blood pressure. Prior to his appointment Adempas drug the doctor should carefully evaluate the risk in patients with specific accompanying undesirable vasodilator effects of diseases (for example, in patients receiving antihypertensive therapy or with underlying arterial hypotension, hypovolemia, severe obstruction of the outflow tract of the left ventricle, or autonomic dysfunction). The combined use of with other drugsSimultaneous use of the drug Adempas with potent inhibitors of the cytochrome and P-gp / BCRP, such as azole antifungals (e.g., ketoconazole, itraconazole), or HIV protease inhibitors (such as ritonavir), not recommended due to the pronounced strengthening effect of the drug Adempas (see. “interaction with other medicinal products and other forms of interaction” section). The simultaneous use of the drug Adempas with potent inhibitors of isoenzyme of CYP1A1, such as a tyrosine kinase inhibitor erlotinib, and potent inhibitors of P-gp / BCRP, such as the immunosuppressant cyclosporin a, may Adempas enhance the action of the drug (see. “Interaction with other medicinal products and other forms of interaction” section). These drugs should be used with caution. Should monitor blood pressure and to consider drug dose reduction Adempas. Populations of patients, studies were performed in which no Adempas has not been studied in these patient groups, and thus, its use is contraindicated have:

  • Patients with systolic blood pressure less than 95 mmHg. Art. at start of treatment;
  • Patients with severe hepatic insufficiency (more than 9 points on a scale Child-Pugh Class C);
  • patients with severely impaired renal function (creatinine clearance less than 15 mL / min) or receiving dialysis. Information for specific groups of patients who smoke effect riotsiguata patients is reduced by 50-60% (see. section “Pharmacokinetic properties”). Such patients are strongly encouraged to quit smoking.

    Effects on ability to drive vehicles, machinery

    Reported cases of dizziness in some patients (see. Section “Side effects”), therefore caution should be exercised when driving and operating other machines.

    release Form

    Film-coated trenbolone hexahydrobenzylcarbonate, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg.
    In 21 of the tablet in the blister with aluminum foil and polypropylene, 2 or 4 blisters with instructions for use placed in a cardboard box.

 

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