Terlipressin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TERLIPRESSIN (TERLIPRESSIN)

Composition:

Active substance: terlipressin;

1 ml of injection solution contains terlipressin acetate 0.12 mg, equivalent to terlipressin 0.1 mg;

Excipients: sodium acetate trihydrate; glacial acetic acid; sodium chloride; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Posterior pituitary hormones. Vasopressin and analogues.

ATC code H01B A04.

Pharmacological Properties

Pharmacodynamics

Terlipressin (N-triglycyl-8-lysine-vasopressin) is a synthetic analogue of vasopressin, a natural hormone of the posterior pituitary gland, differing from vasopressin by substitution of arginine with lysine at position 8 and by the addition of three glycine residues to the terminal amino group of cysteine. The pharmacological action of terlipressin results from the combined effects of active substances formed as a result of its enzymatic cleavage. The most prominent effects of terlipressin are pronounced vasoconstrictive and antihemorrhagic actions. The most significant effect in this regard is reduction of blood flow in the parenchyma of internal organs, leading to decreased hepatic blood flow and portal venous pressure.

Pharmacodynamic studies have shown that, similar to other related peptides, terlipressin induces spasm of arterioles, veins, and venules predominantly in the parenchyma of internal organs, causes contraction of the smooth musculature of the esophageal wall, and increases intestinal tone and peristalsis overall.

In addition to its effects on vascular smooth muscle, terlipressin stimulates uterine smooth muscle, including in the absence of pregnancy.

Studies of the drug's effects in animals and humans have shown maximum activity in internal organs and skin.

No clinical manifestations of antidiuretic effect of terlipressin have been observed.

Pharmacokinetics

Terlipressin itself is inactive on smooth muscle but serves as a chemical depot for pharmacologically active substances formed via enzymatic cleavage. This effect develops more slowly than that of lysine-vasopressin but lasts significantly longer.

Lysine-vasopressin is generally subject to biotransformation in the liver, kidneys, and other tissues.

The pharmacokinetic profile after intravenous administration is best described by a two-compartment model. The elimination half-life is approximately 40 minutes, metabolic clearance is about 9 mL/kg/min, and the volume of distribution is approximately 0.5 L/kg. Detectable plasma concentrations of lysine-vasopressin are typically observed about 30 minutes after administration of terlipressin. Maximum concentration is reached between 60 and 120 minutes.

Clinical characteristics.

Indications.

Gastrointestinal and urogenital bleeding, for example, bleeding from esophageal varices, gastric and duodenal ulcers; uterine bleeding caused by functional disorders or other reasons, childbirth, abortion, etc.; bleeding associated with surgical interventions, particularly in abdominal organs and pelvic cavity.

Locally – during gynecological procedures on the cervix.

Contraindications.

Hypersensitivity to the active substance or to any excipient of the drug. Septic shock in patients with low cardiac output. Pregnancy.

Interaction with other medicinal products and other forms of interaction.

Terlipressin potentiates the effect of non-selective beta-adrenoblockers regarding reduction of portal hypertension.

Concomitant use with drugs causing bradycardia (such as propofol, sufentanil) may lead to decreased heart rate and cardiac output. These effects are due to reflex inhibition of cardiac activity via the vagus nerve and increased arterial pressure.

Special precautions.

When treating with the medicinal product Terlipressin, arterial pressure, pulse rate, and fluid balance should be monitored. To avoid local necrosis at the injection site, the drug should be administered intravenously. Terlipressin should be used with caution in patients with arterial hypertension and heart diseases. The medicinal product Terlipressin should not be used in patients with septic shock and low cardiac output.

Extreme caution should be exercised when treating elderly patients, as experience with this patient group is limited, and dosage recommendations for this group are not available.

The medicinal product Terlipressin is not a blood substitute for patients with circulating blood volume deficiency.

Since focal necroses have been occasionally observed after administration of terlipressin, intramuscular administration should be avoided, and the undiluted drug should be administered intravenously only in doses of 0.5 mg and higher.

This medicinal product contains sodium.

The amount of sodium depends on the administered dose.

1 ml of solution contains 3.59 mg (0.156 mmol) of sodium, which corresponds to less than 1 mmol of sodium (23 mg) per dose, i.e., practically sodium-free.

If more than 1 mmol of sodium is administered in a single dose, caution should be exercised in patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Use of the medicinal product Terlipressin during pregnancy is contraindicated (see section "Contraindications"). Terlipressin has been shown to cause uterine contractions and increased intrauterine pressure in early pregnancy and may reduce uterine blood flow. Administration of Terlipressin may have harmful effects on pregnancy and the fetus. In rabbits, spontaneous abortions and developmental abnormalities were observed.

It is unknown whether the drug passes into breast milk. There are insufficient data on the passage of terlipressin into breast milk. Risk to breastfed infants cannot be excluded. A decision on whether to continue or discontinue breastfeeding or to continue or discontinue therapy with Terlipressin should be made, taking into account the benefit of breastfeeding for the child and the benefit of terlipressin therapy for the mother.

Ability to influence reaction rate when driving or operating machinery.

Studies on the influence of terlipressin on the ability to drive or operate machinery have not been conducted.

Method of Administration and Dosage.

Adults

Initially, intravenous injection of 2 mg of terlipressin every 4 hours should be administered. Treatment should be continued until 24 hours have passed since bleeding has stopped, but not longer than 48 hours. After the initial dose, the dosage may be adjusted to 1 mg intravenously every 4 hours in patients with body weight < 50 kg or in case of adverse reactions.

Esophageal variceal bleeding in adults: 1 mg (1000 mcg) every 4–6 hours for 3–5 days. To prevent rebleeding, treatment should be continued for 24–48 hours after bleeding has ceased. The drug should be administered intravenously as a bolus or as a short-term infusion. The medicinal product may be used undiluted or diluted with 0.9% sodium chloride solution.

Other types of gastrointestinal bleeding in adults: 1 mg (1000 mcg) every 4–6 hours. The drug may also be used as first-line therapy regardless of surgical intervention when upper gastrointestinal bleeding is suspected.

Visceral organ bleeding in children: usually administered at a dose of 8 to 20 mcg/kg body weight every 4–8 hours. The drug should be administered throughout the entire bleeding period; a general recommendation is to continue administration to prevent rebleeding, as in adults. In the presence of sclerosed esophageal varices, a single bolus dose of 20 mcg/kg body weight should be administered.

Urinary tract hemorrhage: due to differences in endopeptidase activity in blood plasma and tissues, the dosage range is sufficiently broad – from 0.2 to 1 mg, to be administered every 4–6 hours.

For juvenile uterine bleeding, recommended doses are 5 to 20 mcg/kg body weight. The drug should be administered intravenously.

Local use in gynecological procedures on the cervix: 0.4 mg (400 mcg) diluted with 0.9% sodium chloride solution to a volume of 10 mL, administered intracervically and/or paracervically. In this case, the effect of the drug develops within 5–10 minutes. If necessary, the dose may be increased or repeated.

Children. The drug should be used for treatment of children according to the recommended regimen.

Overdose.

The recommended dose (2 mg over 4 hours) should not be exceeded due to the dose-dependent risk of developing severe cardiovascular adverse effects.

To control arterial hypertension that may develop during treatment with the medicinal product Terlipressin, 150 mg of clonidine may be administered intravenously.

To manage bradycardia, atropine should be administered.

Side effects.

The most commonly observed adverse reactions during clinical trials (frequency 1–10%): pallor, increased blood pressure, abdominal pain, nausea, diarrhea, and headache.

The antidiuretic effect of the medicinal product Terlipressin may cause hyponatremia if fluid balance is not controlled.

The frequency of adverse reactions is classified by MedDRA System Organ Classes as follows: common (≥ 1–10%); uncommon (≥ 0.1–1%); rare (≥ 0.01–0.1%).

Cardiac disorders: common – bradycardia; uncommon – atrial fibrillation, ventricular extrasystoles, tachycardia, chest pain, myocardial infarction, fluid overload with pulmonary edema, torsade de pointes, heart failure.

Vascular disorders: common – peripheral vasoconstriction, peripheral ischemia, facial pallor, arterial hypertension; uncommon – intestinal ischemia, peripheral cyanosis, hot flushes.

Respiratory, thoracic and mediastinal disorders: uncommon – respiratory distress, respiratory failure; rare – dyspnea.

Gastrointestinal disorders: common – transient diarrhea, transient spasmodic abdominal pain; uncommon – transient nausea, transient vomiting.

Nervous system disorders: common – headache.

Metabolism and nutrition disorders: uncommon – hyponatremia, if fluid balance is not controlled.

Skin and subcutaneous tissue disorders: uncommon – local skin necrosis.

Pregnancy, puerperium and perinatal conditions: uncommon – impaired uterine contractility, reduced uterine blood flow.

General disorders and administration site conditions: uncommon – necrosis at injection site.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as 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.

Storage conditions.

Store in the original packaging at a temperature of 2 to 8 °C. Do not freeze.

Keep out of the reach of children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products.

Use only recommended solvents (see section "Instructions for use, handling and disposal").

Packaging.

2 ml, 5 ml or 8.5 ml in a vial, 5 vials in a blister, 1 blister in a carton; 8.5 ml in a vial, 1 vial in a carton, or 5 vials in a blister, 1 blister in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska St., Kyiv, 04080, Ukraine.