Adempas 1 mg, 42 pcs.

Pharmacodynamics
Mechanism of action
Riociguat is a stimulator of soluble guanylate cyclase (rGC), an enzyme of the cardiopulmonary system and nitric oxide receptor (N0).
When N0 binds to rGC, the enzyme catalyzes the synthesis of the signal molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in the regulation of processes affecting vascular tone, proliferation, fibrosis and inflammation.
Pulmonary hypertension is associated with endothelial dysfunction, impaired nitric oxide synthesis and insufficient stimulation of the NO-rGC-cGMF metabolic pathway. Riociguat has a dual mechanism of action. It sensitizes cGMF to endogenous NO by stabilizing the NO-cGMF bond. Ryociguat also directly stimulates rGC through a different binding site, independent of N0.
Riociguat restores the NO-rHC-cGMF metabolic pathway and causes an increase in cGMF production.
Efficacy in patients with chronic thromboembolic pulmonary hypertension (CTEH)
Efficacy was evaluated 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 CTEH after pulmonary endarterectomy (World Health Organization, WHO, group 4). The study enrolled 261 patients with different disease severity (functional classes, FC), of them 31% of patients were classified as WHO functional class II (WHO FC I), 64% – WHO FC III, with mean distance in 6-min walk test (6MHT, 150-450 m) 347 m.
Primary efficacy endpoint: change in distance in 6MHT by 16 weeks compared to baseline
During treatment, results were achieved:

• change in 6MHT distance by 16 weeks in the riociguat group by 46 m compared with placebo (p<0.0001);
• significant reduction in pulmonary vascular resistance (PVR) p<0.0001, placebo-correlated mean change from baseline -246 din×s×sm-5; 95% confidence interval (CI) from -303 to -190; p<0.0001; Significant decrease in N-terminal fragment of brain natriuretic peptide (NT-proBNP), placebo-correlated mean change from baseline -444 ng/L, CI of -843 to -45 in the riociguat group compared with placebo;
• significant improvement of at least one FC at 16 weeks in the riociguat group in 33% of patients, 15% in the placebo group; decrease of at least one FC in 5% of patients in the riociguat group, 7% in the placebo group (p = 0.0026). FC unchanged in 62% of patients in the riociguat group, 78% in the placebo group.
  There was an improvement in hemodynamic parameters in the riociguat group compared with placebo: statistically significant reduction in LSS, mean pulmonary artery pressure (cPLA) (minus 5.0 mm Hg, p<0.0001) and an increase in cardiac index (CI) of 0.47 l/min/m2; (p<0.0001). Long-term treatment of CHELH (CHEST-2) included 237 patients who completed the CHEST-1 study. The mean duration of treatment at the time of the data cutoff was 388 days. In the CHEST-2 study, further improvements were observed on the 6MHT and FC distance side. The one-year survival rate was 98%.
  Efficacy in patients with pulmonary arterial hypertension (PAH)
  Efficacy was evaluated in a randomized, double-blind, international, multicenter, placebo-controlled phase III study (PATENT-1) involving 443 patients (baseline clinical status: 42% FK II, 54% FK III according to WHO classification, mean distance in 6MHT (150 – 450 m) 363 m) untreated or receiving therapy with endothelin receptor antagonists (ERA) or prostacyclin analog (AP) (inhaled, oral, or subcutaneous). The patient population included men and women aged 18 to 80 years; 61% were idiopathic LAH, 2% were hereditary LAH, 25% were LAH associated with connective tissue diseases, 8% were LAH associated with congenital heart disease, 3% were LAH associated with portal hypertension, and 1% were LAH associated with anorectics or amphetamine use (WHO group 1).
  Primary efficacy endpoint: distance change in 6MXT by 12 weeks
  Treatment achieved outcomes:
• change in distance 6.MHT by 12 weeks in the riociguat group by 36 m compared with placebo (p<0.0001);
• significant decrease in LSS p<0.0001, placebo-correlated mean change from baseline -226 din×s×sm-5; 95% CI -281 to -170; p<0.0001;
• significant decrease in NT-proBNP placebo-correlated mean change from baseline -432 ng/L, 95% CI -782 to -82 in riociguat group compared with placebo;
• timeliness of clinical deterioration was observed in the riociguat group (p=0.0046; stratified log-rank criterion);
• significantly fewer manifestations of clinical deterioration by 12 weeks in the riociguat group (1.2%) vs. placebo (6.3%) (p=0.0285, Mantel-Henzel criterion);
• Borg dyspnea score: significant improvement (-0.4 for riociguat versus +0.1 for placebo; p=0.0022).
  There was an improvement in hemodynamic parameters in the riociguat group compared with placebo: sDLA (minus 3.8 mm Hg, p<0.0001) and increased SI (by 0.56 l/min/m2; p<0.0001).
  Long-term treatment of LAH (PATENT-2) included 363 patients who completed the PATENT-1 study. Mean: duration of treatment at the time of data cutoff was 438 days. In the PATENT-2 study, further improvements were observed on the 6MCHT and FC distance side. The one-year survival rate was 96%.

  Pharmacokinetics
  Absorption
  Absolute bioavailability of riociguat is high (94%). Riotsiguat is quickly absorbed, maximum plasma concentration (Cmax) is reached 1-1.5 hours after oral administration. Absorption of riociguat occurs throughout the gastrointestinal tract (GIT), mainly in the upper regions. Absorption decreases in the distal parts of the gastrointestinal tract. Administration of the drug simultaneously with meals had no effect on the area under the pharmacokinetic curve “concentration-time” (AUC) of riociguat, Cmax decreased to the minimum limit (35% reduction).
  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.
  The volume of distribution is medium, with approximately 30 liters in equilibrium.
  Metabolism
  N-demethylation, catalyzed by the CYP1A1, CYP3A4, CYP2C8, and CYP2J2 isoenzymes, is the major metabolic pathway of riociguat, resulting in its major circulating metabolite (pharmacological activity: 1/10 to 1/3 of riociguat), which is further metabolized to pharmacologically inactive N-glucuronide.
  CYP1A1 isoenzyme catalyzes the formation of the main metabolite of riociguat in the liver and lungs. This process is enhanced by polycyclic aromatic hydrocarbons, such as those found in cigarette smoke (see section “Special Precautions”).
  Excretion
  All riociguat (initial drug and metabolites) is excreted by the kidneys (33-45%) and through the intestine (48-59%). About 4 to 19% of administered dose is excreted unchanged by kidneys, about 9-44% – through the intestines.
  On the basis of in vitro data it was established that ryociguat and its main metabolite are substrates for P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein) transport proteins. Riociguat is a drug 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
  Elderly patients (65 years and older) had higher plasma concentrations of riociguat than younger patients, with AUC values approximately 40% higher in older patients, primarily due to seemingly lower total and renal clearance (see “Administration and Doses” section).
  Patients with impaired liver function
  In patients with cirrhosis accompanied by a mild degree of liver failure (5-6 points on the Child-Pugh score, grade A) no clinically significant changes in the drug action were observed.
  In patients with cirrhosis accompanied by moderate hepatic impairment (7-9 Child-Pugh scores, grade B), mean AUC of riociguat increased by 50-70% compared to healthy volunteers from the control group (see section “Dosage and administration”).
  Administration of riociguat in patients with severe hepatic impairment (10-15 points on the Child-Pugh score, grade C) is contraindicated, since there are no clinical data for such patients (see section “Contraindications”).
  Patients with impaired renal function
  In patients with renal impairment compared to patients with normal renal function, the average dose-normalized and intensity-of-action values of riociguat were higher. Corresponding values for the main metabolite were higher in patients with renal insufficiency compared to healthy volunteers. In patients with creatinine clearance of 80-50 ml/min, 49-30 ml/min and less than 30 ml/min the concentration of riociguat in plasma (AUC) was increased by 43 %, 104 % or 44 %, respectively (see section “Dosage and administration”).
  There are no data for patients with creatinine clearance less than 15 ml/min or those on hemodialysis. Therefore, the drug is contraindicated in patients with creatinine clearance less than 15 ml/min or on hemodialysis (see section “Contraindications”).
  Since ryociguat has a high degree of binding to blood plasma proteins, the possibility of its excretion by dialysis seems unlikely.
  Gender, ethnicity, body weight
  No significant differences in efficacy of riociguat were found depending on the gender, ethnic group or body weight of the patient.

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Indications

Active ingredient

Composition

Contraindications