Pharmacological properties
Pharmacodynamics. Urapidil leads to a decrease in systolic and diastolic pressure by reducing the OPSS. Heart rate remains practically unchanged. Cardiac output does not change; cardiac output, which is reduced due to increased afterload, may increase.
Mechanism of action. Urapidil has a central and peripheral mechanism of action.
At the peripheral level, urapidil blocks mainly postsynaptic α 1 -adrenoreceptors, thus inhibiting the vasoconstrictor effect of catecholamines.
At the central level, urapidil modulates the activity of the circulatory regulation center, which prevents a reflex increase in the tone of the sympathetic nervous system or a decrease in the tone of the vascular bed.
Pharmacokinetics. Absorption. After oral administration, more than 80-90% of urapidil is absorbed in the gastrointestinal tract. C max in the blood plasma of the prolonged-release dosage form is achieved 4-6 hours after administration; T ½ from blood plasma is about 4.7 hours (3.3-7.6 hours).
After intravenous administration of 25 mg of urapidil, a two-phase decrease in the concentration of the drug in the blood was noted (initial distribution phase, terminal elimination phase). The half-life is about 35 min. T ½ of the drug from blood plasma after intravenous bolus administration is 2.7 h (1.8-3.9 h).
Bioavailability. The relative bioavailability of the extended-release capsules compared to the oral solution is 92 (83-103)%. The absolute bioavailability of the extended-release capsules compared to the intravenous standard is 72 (63-80)%.
The in vitro plasma protein binding of urapidil (human serum) is 80%. This relatively low plasma protein binding of urapidil may explain why interactions between urapidil and highly protein-bound drugs are unknown to date.
Distribution. The volume of distribution is 0.77 l/kg body weight. The substance penetrates the blood-brain barrier and the placenta.
Metabolism. Urapidil is metabolized mainly in the liver. The main metabolite - urapidil, hydroxylated in the 4th position of the benzene ring, does not exhibit significant antihypertensive activity. O-dimethylated urapidil - a metabolite that exhibits almost the same biological activity as urapidil, but is formed in very small quantities.
Excretion and elimination. Elimination of urapidil and its metabolites in the human body is up to 50-70% renal, of which about 15% of the dose is pharmacologically active urapidil; the rest, primarily p-hydroxylated urapidil, which does not exhibit an antihypertensive effect, is excreted in the feces.
Special patient groups. In elderly patients, as well as patients with progressive hepatic and/or renal insufficiency, the volume of distribution and clearance of urapidil are reduced, and T½ from blood plasma is increased.
Indication
Ebrantil, capsules. ag.
Ebrantyl, solution for injection. Hypertensive crisis. Severe or very severe hypertension. Refractory hypertension. Controlled lowering of blood pressure in case of its increase during/or after surgery.
Application
Ebrantyl, capsules. For gradual reduction of ad the recommended dose is 30 mg 2 times a day (2 capsules of Ebrantyl 30 mg/day). For rapid reduction of ad treatment is started with a dose of 60 mg 2 times a day (2 capsules of Ebrantyl 60 mg/day).
The dose can be gradually adjusted to individual needs. The maintenance dose range is 60-180 mg/day, the total daily dose divided into 2 doses.
Ebrantyl capsules are taken twice a day, in the morning and evening, during meals, swallowed whole with a small amount of liquid.
Ebrantyl is used for long-term treatment. Treatment of hypertension with the drug requires regular medical monitoring.
Special patient groups
Hepatic impairment: Patients with hepatic impairment may require a reduced dose of Ebrantyl.
Renal impairment: Patients with moderate to severe renal impairment may require a reduced dose of Ebrantyl during long-term treatment.
Elderly patients. Elderly patients may require a reduced dose of Ebrantyl during long-term treatment.
Ebrantyl solution for injection
Hypertensive crisis, severe or very severe hypertension, refractory hypertension
1. Intravenous injection: 10-50 mg of urapidil is administered slowly intravenously under constant monitoring of blood pressure. A decrease in blood pressure is noted within 5 minutes after injection. Parenteral therapy can be repeated with repeated increases in blood pressure.
2. Slow IV drip infusion or continuous infusion using a perfusion device.
The infusion solution intended to maintain blood pressure at the level achieved by injection is prepared as follows: add 250 mg of Ebrantyl to 500 ml of a compatible infusion solution (for example, 0.9% sodium chloride solution or 5% or 10% glucose solution).
If a perfusion device is used to administer the maintenance dose, 20 ml of the injection solution (100 mg of Ebrantyl) is injected into the perfusion device syringe and diluted to a volume of 50 ml with a compatible infusion solution (see above).
The maximum permissible ratio is 4 mg of urapidil per 1 ml of infusion solution.
Rate of administration: The rate of drip administration depends on the individual blood pressure response.
Maintenance dose: an average of 9 mg/h, i.e. 250 mg of urapidil when added to 500 ml of infusion solution (1 mg = 44 drops = 2.2 ml).
Controlled blood pressure lowering to manage hypertensive episodes during/or after surgery. Continuous infusion via a perfusor or drip infusion should be used to maintain blood pressure at the level achieved by injection.
Ebrantyl solution should be administered intravenously to the patient in the supine position, by injection or infusion.
Single or repeated injections and IV drip infusions are possible. Injection of the drug is compatible with subsequent drip infusion. Emergency parenteral therapy can be continued by switching to long-term treatment with Ebrantyl modified-release capsules (initial recommended dose: 2 x 60 mg) or other oral antihypertensive agents. The treatment period of 7 days is considered safe from a toxicological point of view and is usually not exceeded with parenteral antihypertensive therapy. Parenteral therapy can be repeated with repeated increases in blood pressure.
Contraindication
Hypersensitivity to the active substance or any of the excipients of the drug.
For Ebrantyl, solution for infusions also - aortic stenosis, arteriovenous shunts (except for patients with hemodynamically insignificant dialysis shunt).
Side effects
Most of these side effects are due to a sharp decrease in blood pressure, but clinical experience shows that they disappear within a few minutes, even after drip infusion. In case of severe side effects, the drug should be discontinued.
The frequency of occurrence is classified into the following categories: very common (≥1:10), common (≥1:100, 1:10), uncommon (≥1:1000, 1:100), rare (≥1:10,000, 1:1000), very rare (1:10,000), unknown (available data do not allow to estimate the frequency).
On the part of the cardiovascular system: infrequently - palpitations, tachycardia, bradycardia, a feeling of squeezing or pain behind the sternum (symptoms similar to angina pectoris), a decrease in blood pressure when changing body position, for example, when getting up from a lying position (orthostatic dysregulation).
On the part of the digestive system: often - nausea; infrequently - vomiting, diarrhea, dry mouth.
General disorders and administration site conditions: uncommon - fatigue; very rare - edema due to increased fluid retention.
Investigations: very rare - transient increase in liver enzymes, thrombocytopenia*.
From the nervous system: often - dizziness, headache.
On the part of the psyche: infrequently - sleep disturbances; very rarely - a feeling of anxiety.
On the part of the kidneys and urinary tract: very rarely - frequent urge to urinate or increased incidence of urinary incontinence.
From the reproductive system and mammary glands: very rarely - priapism.
On the part of the respiratory system: infrequently - nasal congestion.
Skin and subcutaneous tissue disorders: infrequently - allergic reactions, including itching, redness of the skin, rash; unknown - angioedema, urticaria.
* In isolated cases, a decrease in platelet count has been observed in connection with the temporary use of the drug Ebrantyl, but a causal relationship with the use of urapidil cannot be established, for example, using immunological studies.
If any adverse reactions occur, you should consult a doctor.
Special instructions
Ebrantyl should be used with extreme caution:
in heart failure caused by mechanical functional disorders (e.g. aortic or mitral valve stenosis), pulmonary embolism or cardiac dysfunction due to pericardial disorders; in children, since studies have not been conducted for this age group of patients; in patients with impaired liver function; in patients with moderate or severe renal impairment; in elderly patients; in patients who are taking cimetidine in parallel (see Interactions with other drugs).
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take the drug in capsule form.
The drug in capsule form contains sugar, which should be taken into account by diabetics.
In case of previous use of other antihypertensive drugs, urapidil injection should not be used until sufficient time has passed to detect the therapeutic effect of the previously used drug. The dose of Ebrantyl should be reduced accordingly.
Pregnancy and lactation. The drug is not recommended for use during pregnancy and lactation, as there are no relevant clinical data. The drug can be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Animal studies have not shown any signs of fetal harm.
It is not known whether urapidil passes into breast milk, therefore breastfeeding is not recommended during treatment with urapidil.
Ability to influence the speed of reaction when driving vehicles or working with other mechanisms. In individual cases, adverse reactions from the central nervous system (dizziness) may affect the ability to drive vehicles or work with complex machinery. This is especially important at the beginning of treatment, when replacing a drug or when drinking alcohol.
Interactions
The hypotensive effect of Ebrantyl may be enhanced when used simultaneously with α-adrenergic blockers, vasodilators and other antihypertensive agents, as well as in hypovolemia (diarrhea, vomiting) and when taking alcohol.
With simultaneous use of cimetidine, C max of urapidil may increase by 15%.
Currently, there is insufficient information regarding combination therapy with ACE inhibitors, so this treatment is not recommended.
Incompatibility. The drug Ebrantyl solution for injection should not be mixed with alkaline solutions for injection or infusion due to darkening or the formation of a lamellar precipitate in the solution due to the acidic properties of the solution for injection.
Overdose
Symptoms: from the cardiovascular system - dizziness, orthostatic hypotension and collapse; from the central nervous system - increased fatigue and decreased reaction speed.
Treatment: excessive decrease in blood pressure can be reduced by raising the lower extremities in a supine position, replacing BCC, in the absence of effect - the use of vasoconstrictors, which are administered intravenously slowly under the control of blood pressure. In very rare cases, intravenous administration of catecholamines is necessary (for example, 0.5-1.0 mg of adrenaline diluted in 10 ml of 0.9% sodium chloride solution).
Storage conditions
Capsules: in original packaging at a temperature not exceeding 25 °C.
Solution for injection: at a temperature not exceeding 30 °C.
UA / CVM / 1018/0009
