Tachiben®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TACHYBEN® (TACHYBEN®)

Composition:

Active substance: urapidil;

1 ml of solution contains 5 mg of urapidil;

Excipients: hydrochloric acid concentrated; sodium dihydrogen phosphate dihydrate; sodium hydrogen phosphate dihydrate; propylene glycol; sodium hydroxide; hydrochloric acid diluted; water for injections.

Medicinal form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Antihypertensive agents. Antiadrenergic agents with peripheral mechanism of action. Alpha-adrenoreceptor blockers. ATC code C02CA06.

Pharmacological Properties.

Pharmacodynamics.

Urapidil causes a reduction in systolic and diastolic arterial pressure by decreasing peripheral vascular resistance.

Heart rate remains practically unchanged.

Cardiac output is not altered; if cardiac output was previously reduced due to elevated afterload, it may increase.

Urapidil has both central and peripheral mechanisms of action.

• Peripheral action: Urapidil predominantly blocks postsynaptic α1-adrenoceptors, thereby inhibiting the vasoconstrictive effects of catecholamines.
• Central nervous system (CNS) action: Urapidil modulates the activity of brain centers controlling circulation. As a result, reflexive increases in sympathetic nervous system tone are inhibited, or sympathetic tone is reduced.

Pharmacokinetics.

After intravenous administration of a 25 mg dose, a biphasic decline in urapidil concentration in blood serum is observed (an initial distribution phase followed by a terminal elimination phase). The half-life of distribution is approximately 35 minutes; the volume of distribution is 0.8 L/kg (range 0.6–1.2 L/kg).

Urapidil is predominantly metabolized in the liver. The main metabolite is a hydroxylated derivative of urapidil at the fourth position of the phenyl ring, which has virtually no antihypertensive activity. The O-demethylated metabolite is formed in very small amounts and has approximately the same biological activity as urapidil.

In humans, 50–70% of urapidil and its metabolites are excreted in urine (about 15% as pharmacologically active urapidil). The remainder is excreted in feces as metabolites (predominantly as inactive para-hydroxylated urapidil).

The elimination half-life of urapidil in plasma following intravenous bolus administration averages 2.7 hours (range 1.8–3.9 hours). In vitro, binding to human plasma proteins is 80%. This relatively low degree of plasma protein binding explains why, to date, there has been no evidence of drug interactions between urapidil and other agents that are highly bound to plasma proteins.

In patients with severe hepatic and/or renal insufficiency, as well as in elderly patients, the volume of distribution and clearance of urapidil are reduced, and the elimination half-life is prolonged.

Urapidil crosses the blood-brain and placental barriers.

Clinical characteristics.

Indications.

• Hypertensive crisis.
• Severe forms of arterial hypertension.
• Refractory arterial hypertension.
• Controlled reduction of arterial blood pressure in cases of its elevation during and/or after surgical intervention.

Contraindications.

• Hypersensitivity to urapidil or to any of the excipients.
• Aortic stenosis.
• Arteriovenous shunt (except for a hemodynamically inactive shunt used for dialysis).

Interaction with other medicinal products and other forms of interaction.

The hypotensive effect of urapidil may be enhanced when used concomitantly with alpha-adrenoreceptor blockers (including those used for urological indications), vasodilators, and other antihypertensive agents, as well as in conditions of hypovolemia (diarrhea, vomiting) and during alcohol consumption.

Urapidil should be used with caution in combination with baclofen, as baclofen may enhance the hypotensive effect.

Cimetidine, when used concomitantly, inhibits the metabolism of urapidil. The plasma concentration of urapidil may increase by 15%; therefore, in such cases, dose reduction should be considered.

Caution is required when using urapidil concomitantly with the following medicinal products:

• imipramine (enhanced hypotensive effect and risk of orthostatic hypotension);
• neuroleptics (enhanced hypotensive effect and risk of orthostatic hypotension);
• corticosteroids (reduced antihypertensive effect due to sodium and water retention).

As sufficient experience with combination therapy using ACE inhibitors is lacking, such combination is not recommended at present.

Special precautions for use

The drug should be used with caution:

• in heart failure caused by mechanical dysfunction of the heart, for example, aortic or mitral valve stenosis, pulmonary artery embolism, or worsening of cardiac function due to pericardial diseases;
• in patients with hepatic impairment;
• in patients with moderate to severe renal impairment;
• in elderly patients;
• in patients concurrently using cimetidine (see section "Interaction with other medicinal products and other forms of interaction").

If urapidil is not used as first-line antihypertensive therapy, sufficient time should elapse before initiating treatment to account for the effects of previously prescribed antihypertensive drugs. In such cases, therapy should be initiated with a lower dose of urapidil.

Excessively rapid reduction of arterial blood pressure may lead to bradycardia or cardiac arrest.

Since propylene glycol is an ingredient of Tachiben® tablets, symptoms resembling those of alcohol ingestion may occur during treatment.

One dose of the drug contains a very small amount of sodium – less than 1 mmol (23 mg).

Use during pregnancy or breastfeeding

Urapidil is not recommended during pregnancy. Adequate data on the use of urapidil in pregnant women are lacking.

Animal studies have demonstrated reproductive toxicity of urapidil without evidence of teratogenicity. However, due to limitations of these studies, the potential risk to humans is unknown.

It is currently unknown whether urapidil is excreted in human breast milk; therefore, breastfeeding should be discontinued during treatment with this drug.

Ability to influence reaction speed while driving or operating machinery

In individual cases, certain adverse reactions from the central nervous system (CNS) (e.g., dizziness) may impair the ability to drive or operate complex machinery. This is mainly observed at the beginning of treatment, when the dose is increased, when switching medications, or when alcohol is consumed concurrently.

Method of administration and dosage.

Hypertensive crisis, severe forms of arterial hypertension, refractory arterial hypertension

Intravenous injections: 10–50 mg of urapidil administered intravenously slowly with continuous monitoring of arterial pressure (AP). A reduction in arterial pressure can be expected within 5 minutes after injection. Depending on the clinical effect, repeated intravenous administration of the drug (in a dose of 10–50 mg of urapidil) is possible.

Intravenous drip infusion or infusion using an infusion pump: To maintain arterial pressure at the level achieved after injections, administer the drug by infusion.

Preparation of infusion solution:

• Intravenous drip infusion: Add 250 mg of urapidil (50 mL of the drug) to 500 mL of 0.9% sodium chloride infusion solution or 5% or 10% glucose infusion solution.
• Intravenous infusion using an infusion pump: Draw 100 mg of urapidil (20 mL of the drug) into the infusion pump and dilute to a total volume of 50 mL with 0.9% sodium chloride infusion solution or 5% or 10% glucose infusion solution.

The drug must be diluted under aseptic conditions.

Before administration, visually inspect the solution for discoloration and presence of particulate matter. Only clear, colorless solutions free from particulate matter may be used.

The concentration of the infusion solution must not exceed 4 mg of urapidil/mL.

The infusion rate should be adjusted according to the individual blood pressure response. The recommended initial infusion rate is no more than 2 mg/min.

Maintenance dose – on average 9 mg/h. When diluting 50 mL of the drug (250 mg of urapidil) in 500 mL of diluent, 1 mg = 44 drops = 2.2 mL.

Controlled reduction of arterial pressure during and/or after surgical procedures

Dosage regimen:

Note

The drug should be administered intravenously to patients lying in a supine position. The dose may be given as a single or multiple injections or by slow intravenous infusion. Injections may be combined with subsequent slow infusion.

Treatment of elderly patients

Antihypertensive agents should be used with caution in elderly patients and initiated at low doses, as the sensitivity of elderly patients to drugs of this pharmacotherapeutic class is often altered.

Treatment of patients with renal and/or hepatic impairment

Dosage reduction of urapidil may be required in patients with renal and/or hepatic impairment.

Duration of therapy

Parenteral therapy lasting up to 7 days has been shown to be safe from a toxicological standpoint. The duration of parenteral antihypertensive therapy should generally not exceed this period.

In case of recurrent elevation of blood pressure, parenteral therapy may be repeated.

Initiation of regular oral antihypertensive treatment may occur during the course of emergency parenteral therapy with urapidil.

Children.

Safety and efficacy of intravenous urapidil administration in children (under 18 years of age) have not been established.

Overdose.

Symptoms: dizziness, orthostatic hypotension and collapse, as well as fatigue and drowsiness.

Treatment of overdose: in case of excessive reduction in arterial blood pressure, the patient should be placed in a horizontal position with low head elevation, and infusion therapy should be initiated to increase circulating blood volume. If these measures are insufficient, vasoconstrictors should be administered slowly intravenously under arterial pressure monitoring. In isolated cases, administration of catecholamines may be necessary (e.g., adrenaline 0.5–1.0 mg diluted in 10 ml of isotonic sodium chloride solution).

Side effects.

Most adverse effects are related to too rapid reduction of arterial blood pressure. However, clinical experience shows that these effects resolve within a few minutes, even during continued infusion of the drug; therefore, the decision to discontinue therapy should depend on the severity of the adverse effect.

Adverse reactions are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (available data do not allow estimation of frequency).

Cardiovascular system

Uncommon: palpitations, tachycardia, bradycardia, sensation of pressure or chest pain (symptoms similar to angina pectoris), dyspnea, orthostatic dysregulation (decrease in arterial blood pressure upon change in body position, e.g., when standing up from a lying position).

Gastrointestinal tract

Common: nausea.

Uncommon: vomiting.

General disorders and administration site reactions

Uncommon: increased fatigue, changes at the site of administration.

Investigations

Uncommon: arrhythmias.

Very rare: thrombocytopenia*.

Nervous system

Common: dizziness, headache.

Psychiatric disorders

Very rare: anxiety.

Reproductive system and breast

Rare: priapism.

Respiratory, thoracic and mediastinal disorders

Rare: nasal congestion.

Skin and subcutaneous tissue disorders

Uncommon: increased sweating.

Rare: symptoms of skin allergic reactions (itching, rash, skin redness).

Frequency not known: angioneurotic edema, urticaria.

* In isolated cases, a decrease in platelet count has been observed during treatment with the drug, although a causal relationship with the use of urapidil has not been established, e.g., by immunohematological investigations.

Shelf life.

The medicinal product in the original packaging – 3 years.

After opening the ampoule, the drug and infusion solution remain chemically and physically stable for 50 hours when stored at 15–25 °C.

From a microbiological standpoint, the drug or infusion solution should be used immediately. If not used immediately, storage duration and conditions should be controlled by the responsible person. Generally, the storage time of solutions should not exceed 24 hours at 2–8 °C, unless all manipulations were performed under controlled and validated aseptic conditions.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach of children.

Incompatibilities.

The drug should not be mixed with other medicinal products except 0.9% sodium chloride infusion solution or 5% or 10% glucose infusion solution.

Alkaline injection and infusion solutions should not be used simultaneously, as this may cause clouding of the solution, formation of flakes or precipitate.

Packaging.

5 ml in a clear glass ampoule; 5 ampoules in a cardboard box.

10 ml in a clear glass ampoule; 5 ampoules in a cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorization Holder.

EVER Neuro Pharma GmbH, Austria.

Address of manufacturer and location of its operations / Address of marketing authorization holder.

Oberburgau, 3, 4866 Unterach am Attersee, Austria.