Rioziguat - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other cardiovascular drugs

Included in the formulation

Adempas

pills inwards

Bayer Pharma AG Germany

АТХ:

C.02.K.X Other antihypertensive drugs

C.02.K.X.05 Riotsiguat

Pharmacodynamics:

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. Riotsiguat has a double mechanism of action. It sensitizes cGMP to endogenous NO by stabilizing NO-cGMP binding. 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.

Pharmacokinetics:

Absolute bioavailability of riotsiguata is high (94%). Riotsiguat quickly absorbed, the maximum concentration in the blood plasma (Cmax) is reached after 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.Use of the drug simultaneously with food intake did not influence the value of the area under the curve "concentration-time" (AUC) riotsiguata, Cmax was reduced to a minimum limit (35% reduction). All riotsiguat (initial 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.

Indications:

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

- Inoperable HTELG;

- persistent or relapsing CTEPH after surgical treatment.

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

- Idiopathic PAH;

- hereditary PAH;

- LAS, associated with connective tissue diseases.

ICD-10

IX.I26-I28.I27.0 Primary pulmonary hypertension

IX.I26-I28.I27.8 Other specified forms of pulmonary heart disease

Contraindications:

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

- pregnancy and the period of breastfeeding;

- age up to 18 years;

- simultaneous reception with nitrates or donators of nitric oxide (such as amyl nitrite) in any dosage form;

- simultaneous use with the drugs of the group of phosphodiesterase (PDE) inhibitors, including with preparations 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 violations of the liver (more than 9 points on the scale Child-Pugh, Class C, experience in clinical use is absent);

- severe arterial hypotension at the time of initiation of therapy (systolic blood pressure less than 95 mm Hg, clinical experience is not available);

- 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 (cf.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 CYP1A1 isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and strong inhibitors of P-gp / BCRP, such as an immunosuppressive drug ciclosporin A (see the section "Interaction with other medicinal products 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 liver function (7-9 points on the Child-Pugh scale, class B);

- in elderly patients (65 years and older).

Pregnancy and lactation:

Adequate and controlled studies in humans are not conducted. During the treatment of the drug, women of reproductive age should use effective methods of contraception. There is no information about the penetration into human milk of a man, but penetrates into the milk of animals. Do not apply!

Recommendations FDA category C.

Dosing and Administration:

For oral administration.

Rioziguat can 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 times daily for 2 weeks. Tablets should be taken three times a day at intervals of about 6-8 hours, at the same time as eating or regardless of the time of ingestion.

The maximum daily dose of the drug 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.

Side effects:

Violations from the blood and lymphatic system: often anemia (including relevant laboratory indicators).

Impaired nervous system: very often - dizziness, headache.

Violations from the heart and blood vessels: often - heart palpitations, lowering blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: often - hemoptysis, nosebleeds, nasal congestion, infrequent - pulmonary hemorrhage.

Disorders from the digestive tract: very often - dyspepsia, diarrhea, nausea, vomiting, often - gastritis, gastroenteritis, gastroesophageal reflux disease, dysphagia, pain in different parts of the digestive tract, constipation, bloating.

General disorders and disorders at the site of administration: very often peripheral edema.

Overdose:No data.

Interaction:

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 of 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.

Drugs that strongly inhibit P-gp / BCRP, such as an immunosuppressant ciclosporin A, should be applied with caution.

Simultaneous use of drugs that increase the pH of the gastrointestinal tract may lead to a lower bioavailability when taken orally, since the solubility of riotsiguata decreases at a neutral pH compared to an acidic environment.

The simultaneous use of riotsiguata and nitrates or donators of nitric oxide (such as amyl nitrite) in any dosage form is contraindicated.

In animal studies, a reduction in systemic arterial pressure was shown in the combination of riotsiguata with sildenafil or vardenafil.

Special instructions:

Application of the drug riotsiguat in patients with venous occlusion disease of the lung (VOBL) is not recommended, because 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 a drug riotsiguat in this case should be terminated.

In patients with pulmonary hypertension there is an increased chance of bleeding from the respiratory tract, especially among patients receiving anticoagulant therapy.

When treating the drug riotsiguat 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.

Rioziguat has vasodilator properties, which can lead to lowering blood pressure. Before prescribing riotsiguat the physician should carefully evaluate the risk of developing adverse events in patients with specific concomitant diseases.vasodilator effects (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 use of riotsiguata 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 riotsiguata.

Simultaneous use of the riotsiguata preparation with strong inhibitors of the CYP1A1 isoenzyme, such as a tyrosine kinase inhibitor erlotinib, and strong inhibitors of P-gp / BCRP, such as an immunosuppressant ciclosporin A, can enhance the action of riotsiguata. These drugs should be used with caution. It is necessary to control blood pressure and consider the possibility of reducing the dose of riotsiguata.

Populations of patients, studies in which were not conducted

Rioziguat has not been studied in the following patient groups, 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.

Instructions

Riotsiguat (Riociguat)