Terlipressin-pharmak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TERLIPRESSIN-FARMAK (TERLIPRESSIN-FARMAK)

Composition:

Active substance: terlipressin;

1 ml of injection solution contains terlipressin acetate 0.2 mg, equivalent to terlipressin 0.17 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 has low pharmacological activity; however, it is metabolized to the active form, lysine-vasopressin, via enzymatic hydrolysis. Doses of 0.85 mg and 1.7 mg reduce portal venous pressure and induce pronounced vasoconstriction. Reduction in portal vein pressure and decreased blood flow in the azygos vein are dose-dependent. The effect of the lower dose diminishes after 3 hours, whereas hemodynamic data indicate that the 1.7 mg dose of terlipressin is more effective than 0.85 mg, as the higher dose provides a more reliable effect throughout the treatment period (4 hours).

Terlipressin reduces portal hypertension by simultaneously decreasing portal blood flow and induces esophageal smooth muscle spasm, resulting in compression of esophageal varices.

Biologically active lysine-vasopressin is slowly released from the inactive prohormone terlipressin and remains within a concentration range from minimally active to subtoxic for 4–6 hours, as metabolic elimination of lysine-vasopressin occurs in parallel with its release.

Terlipressin increases smooth muscle tone in the gastrointestinal tract both within and outside blood vessels. Due to increased peripheral resistance in terminal arterioles, reduced trophism of nerve fibers innervating internal organs is observed. Decreased arterial blood inflow leads to reduced pressure in the portal venous system. Concurrent contraction of muscular layers in various intestinal segments enhances peristalsis. Additionally, contraction of esophageal wall muscles compresses varicose nodules.

The antidiuretic activity of terlipressin is only 3% of that of native vasopressin. This activity is not clinically significant. Under normovolemic conditions, renal blood flow does not significantly change. However, in the presence of hypovolemia, renal blood flow increases.

Terlipressin exerts a slow hemodynamic effect over 2–4 hours. Slight increases in both systolic and diastolic arterial pressure occur. In cases of renal hypertension and generalized angiogenesis, significant elevation in arterial pressure has been observed.

Terlipressin has not caused any cardiotoxic effects, even when higher doses were administered. Cardiac effects such as bradycardia, arrhythmia, and coronary insufficiency may occur as a result of reflex or vascular effects of terlipressin.

Under the influence of terlipressin, blood flow in the endometrium and myometrium is significantly reduced.

The vasoconstrictive effect of terlipressin leads to inadequate skin perfusion and thus causes noticeable pallor of the patient's skin.

Hemodynamic effects and action on smooth muscle are the primary manifestations of terlipressin's pharmacological activity. The effect of centralization of circulation during hypovolemia is a desirable side effect in patients with bleeding from esophageal varices.

Pharmacokinetics.

The plasma elimination half-life of terlipressin is 24 ± 2 minutes.

Terlipressin has weak pharmacological activity. After intravenous bolus administration, terlipressin is eliminated according to second-order kinetics. The plasma half-life during the distribution phase (duration up to 40 minutes) is 12 minutes. Upon cleavage of the free glycine residue, the hormone lysine-vasopressin is slowly released and reaches peak concentration at 120 minutes. Only 1% of the administered terlipressin is excreted in urine, indicating nearly complete degradation of the drug by endo- and exopeptidases of the liver and kidneys.

Clinical characteristics.

Indications.

Bleeding from esophageal varices.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Terlipressin enhances the hypotensive effect of non-selective beta-blockers on the portal vein. The reduction in heart rate and cardiac output caused by treatment can be explained by inhibition of reflex cardiac activity via the vagus nerve due to increased arterial pressure. Concomitant use with medicinal products that cause bradycardia (such as propofol, sufentanil) may lead to severe bradycardia.

Terlipressin may induce ventricular arrhythmias, including torsades de pointes. Therefore, terlipressin should be used with caution in patients receiving medicinal products that may prolong the QT interval, such as class IA and III antiarrhythmic agents, erythromycin, certain antihistamines, and tricyclic antidepressants, or agents that may cause hypokalemia or hypomagnesemia (e.g., certain diuretics).

Special precautions for use.

The use of terlipressin requires caution and careful monitoring of the patient's condition in the following diseases: septic shock, bronchial asthma, respiratory tract diseases, uncontrolled hypertension, cerebral, coronary or peripheral vascular diseases (progressive atherosclerosis), seizures (convulsions), cardiac arrhythmias, cardiovascular diseases, coronary insufficiency or history of myocardial infarction, chronic renal failure. Particular attention should be paid to elderly patients (over 70 years of age), as experience with use in this age group is limited.

In patients with hypovolemia, increased vasoconstriction and atypical cardiac reactions are often observed.

Due to the weak antidiuretic activity of terlipressin (3% of the activity of native vasopressin), the possibility of developing hyponatremia and hypokalemia should be considered, especially in patients with disturbances of water-electrolyte balance.

During treatment, arterial pressure, heart rate, ECG parameters, and fluid balance should be monitored.

The medicinal product Terlipressin-Pharmak should be administered in an intensive care unit setting with careful monitoring of cardiac function.

In emergency situations requiring immediate treatment prior to hospitalization, particular attention should be paid to hypovolemic syndrome.

The medicinal product Terlipressin-Pharmak does not affect arterial bleeding.

To avoid necrosis at the injection site, the drug must be administered intravenously.

Skin necrosis

Several cases of skin ischemia and necrosis, unrelated to the injection site, have been reported during post-marketing use. Patients with peripheral venous hypertension or pathological obesity are more prone to this reaction. Therefore, terlipressin should be administered with great caution in such patients.

Torsades de pointes tachycardia

During clinical trials and post-marketing use, several cases of QT interval prolongation and ventricular arrhythmias, including torsades de pointes tachycardia, have been reported. In most cases, patients had risk factors such as baseline QT prolongation, electrolyte imbalances (hypokalemia, hypomagnesemia), or concomitant use of medicinal products that prolong the QT interval. Terlipressin should be used cautiously in patients with a history of QT interval prolongation, electrolyte imbalances, or when co-administered with medicinal products that may prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines, and tricyclic antidepressants, or medicinal products that may cause hypokalemia or hypomagnesemia (e.g., certain diuretics).

Experience in treating elderly patients is limited; therefore, terlipressin should be used with particular caution in this age group. Dosage recommendations for elderly patients are not available.

There is no experience with the use of the medicinal product Terlipressin-Pharmak in children and adolescents; therefore, the drug should not be used in this age group.

Each 1 ml of the Terlipressin-Pharmak solution contains 3.59 mg (0.156 mmol) of sodium, which corresponds to less than 1 mmol of sodium (23 mg) per dose. Thus, the medicinal product is practically sodium-free. However, if a dose containing more than 1 mmol of sodium is administered, caution should be exercised when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Use of the medicinal product Terlipressin-Pharmak during pregnancy is contraindicated. Terlipressin-Pharmak causes uterine contractions and increases intrauterine pressure in early pregnancy and may reduce uterine blood flow. The medicinal product Terlipressin-Pharmak has a negative effect on the course of pregnancy and fetal health.

In rabbits, spontaneous abortions and fetal organ malformations were observed after treatment with terlipressin.

It is unknown whether the drug is excreted in breast milk. Excretion of terlipressin in breast milk has not been studied in animals. Risk to the nursing infant cannot be excluded.

Breastfeeding should be discontinued during treatment with the medicinal product. The decision on continuing/discontinuing breastfeeding or continuing/discontinuing terlipressin therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of terlipressin therapy for the mother.

Ability to influence reaction speed when driving or operating machinery.

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

Administration and Dosage

The medicinal product Terlipressin-Pharmak is indicated for emergency medical care in cases of acute bleeding from esophageal varices until endoscopic therapy becomes possible. Thereafter, Terlipressin-Pharmak is generally used for the treatment of bleeding from esophageal varices as an adjunctive therapy together with endoscopic hemostatic procedures. Terlipressin-Pharmak may also be used to reduce early rebleeding.

The drug must be administered intravenously.

Initially, 1–2 mg of terlipressin acetate is administered intravenously. The maintenance dose is 1 mg of terlipressin acetate every 4–6 hours. The usual maximum daily dose of Terlipressin-Pharmak is 120 mcg/kg body weight. For an adult patient weighing 70 kg, the daily dose is 8–9 mg of terlipressin acetate, administered at 4-hour intervals.

The duration of treatment is 2–3 days.

Elderly patients

The drug should be used with caution in patients over 70 years of age (see section "Special Warnings and Precautions for Use").

Renal impairment

Terlipressin-Pharmak should be used with caution in patients with chronic renal impairment (see section "Special Warnings and Precautions for Use").

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment.

Children. There is no experience with the use of terlipressin in children; therefore, the drug should not be used in this age group.

Overdose

The recommended dose should not be exceeded due to the dose-dependent risk of developing severe cardiovascular adverse effects.

Elevated arterial pressure in patients with known arterial hypertension can be managed by intravenous administration of 150 mcg of clonidine.

Bradycardia requiring treatment should be managed with atropine.

Adverse Reactions

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

The antidiuretic effect of terlipressin may cause hyponatremia if fluid balance is not carefully monitored.

Frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Cardiac disorders: common — bradycardia, ventricular and supraventricular arrhythmia, signs of ischemia on ECG; uncommon — acute hypertension, particularly in patients with pre-existing hypertension (usually resolves spontaneously), tachycardia, atrial fibrillation, ventricular extrasystoles, angina pectoris, myocardial infarction, fluid overload with pulmonary edema; not known — torsade de pointes tachycardia, heart failure.

Vascular disorders: common — peripheral vasoconstriction, peripheral ischemia, arterial hypertension or hypotension, skin pallor; uncommon — intestinal ischemia, peripheral cyanosis, flushing.

Respiratory system disorders: uncommon — dyspnea, pleuritic pain, chest pain, bronchospasm, respiratory failure, apnea; rare — shortness of breath.

Gastrointestinal disorders: common — nausea, diarrhea, colicky abdominal pain; uncommon — vomiting.

Nervous system disorders: common — headache; uncommon — triggering of epileptic seizures; very rare — apoplexy.

Metabolism and nutrition disorders: common — hyponatremia.

Skin and subcutaneous tissue disorders: common — skin pallor; uncommon — lymphangitis, skin necrosis.

Reproductive system disorders: common — colicky lower abdominal pain (in women).

Pregnancy, puerperium and perinatal conditions: uncommon — increased uterine tone, uterine ischemia.

Administration site conditions: uncommon — injection site necrosis.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging.

Incompatibilities

Since compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products.

Storage conditions.

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

Keep out of the reach and sight of children.

Packaging.

2 ml, 5 ml or 10 ml in an ampoule. 5 ampoules in a blister, 1 blister in a carton.

5 ml or 10 ml in a vial. 1 vial in a carton, or 5 vials in a blister, 1 blister in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.