Urapidil calcex
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT URAPIDIL KALCEKS (URAPIDIL KALCEKS)
Composition:
Active substance: urapidil;
1 ml of solution contains 5 mg of urapidil;
5 ml of solution (1 ampoule) contains 25 mg of urapidil;
10 ml of solution (1 ampoule) contains 50 mg of urapidil;
Excipients: hydrochloric acid concentrated, sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dihydrate, propylene glycol, sodium hydroxide, water for injections.
Pharmaceutical form. Solution for injection and infusion.
Main physicochemical properties: clear, colorless solution.
Pharmacotherapeutic group. Antihypertensive agents. Peripheral antiadrenergic agents. Alpha-adrenoreceptor blockers.
ATC code C02CA06.
Pharmacological properties.
Pharmacodynamics.
Urapidil reduces systolic and diastolic arterial pressure by decreasing peripheral vascular resistance.
Heart rate remains practically unchanged.
Cardiac output also remains unchanged; cardiac output, which may decrease due to increased afterload, may increase.
Mechanism of action. Urapidil is a vasodilating agent with both central and peripheral mechanisms of action.
At the peripheral level, urapidil predominantly blocks postsynaptic alpha1-adrenoreceptors, thereby inhibiting the vasoconstrictive effects of catecholamines.
At the central level, urapidil modulates the activity of the cardiovascular regulatory center, preventing reflex increases in sympathetic nervous system tone or reducing sympathetic tone.
Pharmacokinetics.
Absorption
After intravenous administration of 25 mg of urapidil, a biphasic change in blood concentration is observed (initial distribution phase, final elimination phase).
The distribution phase is characterized by a half-life of approximately 35 minutes.
The plasma half-life after intravenous bolus injection is 2.7 (1.8–3.9) hours.
Protein binding of urapidil to human plasma proteins in vitro is 80%. The relatively low plasma protein binding of urapidil may explain why, to date, no interactions between urapidil and medicinal products highly bound to plasma proteins have been reported.
Distribution
The volume of distribution is 0.77 L/kg body weight. The active substance penetrates the blood-brain barrier and placental barrier.
Metabolism
Urapidil is predominantly metabolized in the liver. The main metabolite is urapidil hydroxylated at the 4-position of the phenyl group, which has no significant antihypertensive activity. The O-demethylated metabolite of urapidil has approximately the same biological activity as urapidil but is formed only to a minor extent.
Excretion and elimination
Renal elimination of urapidil and its metabolites accounts for 50–70%, of which approximately 15% of the administered dose is excreted as pharmacologically active urapidil; the remainder is excreted in feces as metabolites, mainly as para-hydroxylated urapidil, which has no hypotensive effect.
Special populations
In patients with progressive hepatic and/or renal impairment, as well as in elderly patients, the volume of distribution and clearance of urapidil are reduced, and the plasma half-life is prolonged.
Clinical characteristics.
Indications.
- Hypertensive crisis.
- Severe or very severe degree of arterial hypertension.
- Refractory arterial hypertension.
- For controlled reduction of arterial blood pressure when elevated during and/or after surgical intervention.
Contraindications.
- Hypersensitivity to any component of the medicinal product.
- Aortic stenosis.
- Arteriovenous shunt (except for patients with hemodynamically insignificant dialysis shunt).
Interaction with other medicinal products and other types of interactions.
The hypotensive effect of the drug may be enhanced when used concomitantly with alpha-adrenoreceptor blockers, vasodilators, and other antihypertensive agents, as well as in conditions of hypovolemia (e.g., diarrhea, vomiting) and alcohol consumption.
When used concomitantly with cimetidine, an increase in serum urapidil levels by 15% is expected.
Information regarding combination therapy with angiotensin-converting enzyme (ACE) inhibitors is currently insufficient; therefore, such treatment is not recommended.
Special precautions for use.
Special caution is required when using urapidil in the following cases:
- heart failure caused by mechanical or functional disorders (e.g., aortic or mitral valve stenosis), in pulmonary embolism, or impaired cardiac function due to pericardial disorders;
- children, as studies in this patient age group have not been conducted;
- patients with hepatic impairment;
- patients with moderate or severe renal impairment;
- elderly patients;
- patients concurrently using cimetidine (see section "Interaction with other medicinal products and other forms of interaction").
If other antihypertensive agents have been previously administered, sufficient time should elapse to allow for the effects of prior antihypertensive therapy to subside. Therefore, a lower dose of urapidil should be selected. Excessively rapid reduction in arterial pressure may lead to bradycardia or cardiac arrest.
This medicinal product should not be used during pregnancy or lactation unless recommended by a physician. Additional monitoring may be required when this medicine is used under medical supervision.
This medicinal product should not be used in patients with liver or kidney disease unless recommended by a physician. Additional monitoring may be required when this medicine is used under medical supervision.
This medicinal product contains propylene glycol
The propylene glycol contained in this medicinal product may have effects similar to those of alcohol consumption and may increase the likelihood of adverse reactions.
This medicine should be used only under medical advice. Additional monitoring may be required when this medicine is used under medical supervision.
This medicinal product contains sodium
This medicinal product contains less than 1 mmol (23 mg) of sodium per 1 ml of solution, i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding.
Women of reproductive age
This medicinal product is not recommended for women of reproductive age who are not using contraception.
Pregnancy
Currently, there are no data or very limited data on the use of urapidil in pregnant women.
Animal studies have shown reproductive toxicity. Urapidil crosses the placental barrier. This medicinal product should not be used during pregnancy unless the woman's clinical condition necessitates treatment with urapidil.
Lactation period
It is unknown whether urapidil is excreted in breast milk. Therefore, risk to the newborn/infant cannot be excluded. This medicinal product should not be used during breastfeeding.
Fertility
Clinical studies on fertility in men and women have not been conducted. Animal studies have shown that urapidil affects fertility.
Ability to influence reaction speed when driving or operating machinery.
In individual cases, certain adverse reactions of the central nervous system (e.g., dizziness) may affect the ability to drive or operate machinery. This is particularly relevant at the beginning of treatment, during dose escalation, changes in therapy, or concomitant alcohol consumption.
Administration and Dosage
Hypertensive crisis, severe or very severe arterial hypertension, refractory hypertension.
- Intravenous injection
10–50 mg of urapidil are administered slowly intravenously with continuous monitoring of arterial pressure.
Antihypertensive effect is expected within 5 minutes after administration. Depending on the arterial pressure response, the urapidil injection may be repeated.
- Slow intravenous infusion or continuous infusion via infusion pump
A solution for continuous intravenous infusion used to maintain the arterial pressure level achieved after the initial injection is prepared as follows: 250 mg of urapidil are usually added to 500 mL of a compatible infusion solution (see below in this section).
When using an infusion pump for administering the maintenance dose, 20 mL of the injection/infusion solution (= 100 mg of urapidil) are drawn into a syringe and diluted to a final volume of 50 mL with a compatible infusion solution (see below in this section).
The maximum compatible concentration is 4 mg of urapidil per 1 mL of infusion solution.
Infusion rate
The infusion rate should be adjusted according to the individual arterial pressure response.
Recommended initial infusion rate: 2 mg/min.
The degree of arterial pressure reduction is determined by the dose administered during the first 15 minutes. Thereafter, the target arterial pressure can usually be maintained using considerably lower doses.
Maintenance dose: on average 9 mg/hour, based on 250 mg of urapidil in 500 mL of infusion solution, equivalent to 1 mg = 44 drops = 2.2 mL.
Controlled reduction of arterial pressure to manage hypertensive episodes during or after surgery.
Continuous infusion via an infusion pump or drip infusion should be used to maintain arterial pressure at the level achieved after the initial bolus injection.
Dosing regimen
| Intravenous injection of 25 mg of urapidil (= 5 ml of injection/infusion solution) |
If blood pressure reduction occurs |
Blood pressure stabilized by infusion Initial dose up to 6 mg within 1–2 min, then reduce dose |
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For single use only. May be diluted with:
Any unused medicinal product or waste material must be disposed of in accordance with local requirements. Children Clinical data on the efficacy and safety of using the drug in children are lacking. Overdose. Symptoms:
Treatment. Excessive reduction in blood pressure may be alleviated by elevating the lower limbs in the supine position and volume replacement. If these measures are insufficient, vasoconstrictors may be administered slowly intravenously with blood pressure monitoring. In very rare cases, intravenous injection of catecholamines (e.g., 0.5–1.0 mg of adrenaline diluted in 10 ml of 0.9% sodium chloride solution) may be necessary. Adverse reactions.Most of the adverse effects listed below are due to a rapid decrease in blood pressure; however, clinical experience shows that they resolve within a few minutes, even after continuous infusion. In case of severe adverse effects, administration of the drug should be discontinued. Adverse effects are classified by frequency of occurrence 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), unknown (frequency cannot be estimated from available data). Cardiovascular system. Uncommon: palpitations, tachycardia, bradycardia, sensation of pressure or pain behind the sternum (symptoms similar to angina pectoris), dyspnea, decreased blood pressure upon change in body position, e.g., upon standing from a lying position (orthostatic dysregulation). Gastrointestinal tract. Common: nausea. Uncommon: vomiting. General disorders. Uncommon: increased fatigue, injection site reactions. Investigations. Uncommon: irregular heart rhythm. Very rare: thrombocytopenia*. Nervous system. Common: dizziness, headache. Psychiatric disorders. Very rare: feeling of anxiety. Reproductive system and breast. Very rare: priapism. Respiratory system. Rare: nasal congestion. Skin and subcutaneous tissue. Uncommon: increased sweating. Rare: hypersensitivity reactions including itching, skin redness, rash. Unknown: angioedema, urticaria. * Decreased platelet count has been observed in isolated cases during concomitant oral administration of urapidil. A causal relationship with urapidil therapy has not been established, e.g., according to immunohematological tests. If any adverse reactions occur, consult a physician. Reporting suspected adverse reactions. Reporting of adverse reactions after drug authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua. Shelf life. 2 years. Do not use after the expiry date stated on the packaging. Shelf life after dilution Chemical and physical in-use stability has been demonstrated for 50 hours at 25 °C and at 2–8 °C when diluted in 9 mg/ml (0.9%) sodium chloride infusion solution, 50 mg/ml (5%) glucose infusion solution, or 100 mg/ml (10%) glucose infusion solution. From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user and generally should not exceed 24 hours at 2–8 °C, unless dilution has been carried out under controlled and validated aseptic conditions. Storage conditions. No special storage conditions required. Keep out of reach of children. Incompatibilities. Urapidil Kalzeks must not be mixed with alkaline injection or infusion solutions, as cloudiness or precipitation may occur due to the acidic nature of the solution. This medicinal product must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage". Packaging. 5 ml or 10 ml in a vial made of colorless glass of hydrolytic class I, with score marks and a break point. 5 vials in a blister pack made of polyvinyl chloride film. 1 blister pack with the instructions for medical use in a cardboard carton. Prescription status. Prescription only. Manufacturer. Manufacturer responsible for batch release: JSC "Kalzeks". Manufacturer's address and place of business. Krustpils Street 71E, Riga, LV-1057, Latvia. Marketing authorization holder. JSC "Kalzeks". Address of marketing authorization holder. Krustpils Street 71E, Riga, LV-1057, Latvia. | |||
