Glipresin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLYPRESSIN® (GLYPRESSIN®)

Composition:

Active substance: terlipressin acetate;

1 vial contains 1 mg of terlipressin acetate, equivalent to 0.86 mg of free terlipressin;

Excipients: mannitol (E 421), hydrochloric acid 1M;

1 ampoule of solvent contains: sodium chloride, hydrochloric acid 1M, water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white lyophilized powder;

solvent – clear, colorless solution.

Pharmacotherapeutic group. Posterior pituitary hormones. Vasopressin and analogues.

ATC code H01BA04.

Pharmacological properties.

Pharmacodynamics.

Terlipressin has low pharmacological activity; however, it is metabolized into the active form, lysine-vasopressin, via enzymatic hydrolysis. Doses of 0.85 mg and 1.7 mg reduce portal venous pressure and cause pronounced vasoconstriction. Reduction in portal venous 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 while simultaneously decreasing portal blood flow, and induces esophageal 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 perfusion of nerve fibers innervating internal organs is observed. Decreased arterial blood inflow leads to reduced pressure in the portal venous system. Simultaneous contraction of muscular layers in various intestinal segments enhances peristalsis. Furthermore, contraction of esophageal wall muscles compresses varicose veins.

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 blood pressure occur. In cases of renal hypertension and generalized angiosclerosis, a significant rise in arterial pressure has been observed.

Administration of terlipressin has not led to any cardiotoxic effects, even at higher doses. Cardiac effects such as bradycardia, arrhythmia, and coronary insufficiency may occur, possibly due to 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, thus causing visibly apparent pallor of the patient's skin.

Hemodynamic effects and actions on smooth muscle represent the main manifestations of terlipressin's pharmacological activity. The centralizing effect on circulation during hypovolemia is a beneficial 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 min) is 12 minutes. Free glycine residue is released, and the hormone lysine-vasopressin is slowly released, reaching peak concentration at 120 minutes. Only 1% of administered terlipressin is excreted in urine, indicating nearly complete degradation of the drug by hepatic and renal endo- and exopeptidases.

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. 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 taking medicinal products that may prolong the QT interval, such as class IА and III antiarrhythmic agents, erythromycin, certain antihistamines, and tricyclic antidepressants, or drugs that may cause hypokalemia or hypomagnesemia (e.g., certain diuretics).

Special precautions for use

Terlipressin should be used with caution and under close monitoring in patients with the following conditions: 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, as well as in elderly patients (over 70 years of age), since experience with use in this age group is limited.

Patients with hypovolemia often exhibit increased vasoconstriction and atypical cardiac reactions.

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 in water-electrolyte balance.

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

Terlipressin should be administered in an intensive care setting with continuous cardiac function monitoring.

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

Terlipressin does not affect arterial bleeding.

To avoid necrosis at the injection site, administer the drug intravenously only.

Skin necrosis

During post-marketing use, several cases of skin ischemia and necrosis, not related to the injection site, have been reported. Patients with peripheral venous hypertension or pathological obesity are more susceptible 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 predisposing factors such as underlying QT prolongation, electrolyte imbalances (hypokalemia, hypomagnesemia), or concomitant use of drugs that prolong the QT interval. Terlipressin should be used with caution in patients with a history of QT prolongation, electrolyte disturbances, or when co-administered with drugs that may prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines, tricyclic antidepressants, or drugs 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. Dose recommendations for elderly patients are not available.

Experience with the use of terlipressin in children and adolescents is lacking; therefore, the drug should not be used in this age group.

Terlipressin contains less than 1 mmol (23 mg) of sodium per 5 ml of solvent, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

The use of terlipressin during pregnancy is contraindicated.

Terlipressin causes uterine contractions and increases intrauterine pressure in early pregnancy and may reduce uterine blood flow. Terlipressin has a negative effect on pregnancy outcomes 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 human breast milk. Excretion of terlipressin in breast milk has not been studied in animals. Risk to the nursing infant cannot be excluded.

The decision on whether to continue or discontinue breastfeeding or continue or discontinue terlipressin therapy should be made after considering the benefits of breastfeeding for the child and the benefits of terlipressin therapy for the woman. Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery

No studies have been conducted on the effects of terlipressin on the ability to drive vehicles or operate machinery.

Dosage and Administration

Glypressin is used for emergency medical treatment in cases of acute bleeding from esophageal varices until endoscopic therapy becomes possible. Thereafter, Glypressin is typically used as an adjunctive treatment for bleeding from esophageal varices in combination with endoscopic hemostatic procedures. Glypressin may also be used to reduce early rebleeding.

The powder should be dissolved in the solvent provided and administered intravenously slowly. The reconstituted injection solution should be used immediately. Initially, 1−2 mg of Glypressin (1−2 vials) is administered intravenously. The maintenance dose is 1 mg of the drug (1 vial) every 4−6 hours. The usual maximum daily dose of Glypressin is 120 mcg/kg body weight. For an adult patient weighing 70 kg, the daily dose is 8−9 mg of the drug (8−9 vials), administered at 4-hour intervals.

The duration of treatment is 2−3 days.

Elderly Patients

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

Renal Impairment

Glypressin 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 Glypressin in children, and therefore the drug should not be administered to patients in this age group.

Overdose

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

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

Bradycardia requiring treatment should be managed with atropine.

Side effects

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

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

The frequency of adverse reactions is classified 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); 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, cardiac 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, pain on breathing, chest pain, bronchospasm, respiratory failure, apnea;
Rare – shortness of breath.

Gastrointestinal disorders:
Common – nausea, diarrhea, spasmodic abdominal pain;
Uncommon – vomiting.

Nervous system disorders:
Common – headache;
Uncommon – triggering of epileptic seizures;
Very rare – stroke.

Metabolism and nutrition disorders:
Common – hyponatremia.

Skin and subcutaneous tissue disorders:
Common – skin pallor;
Uncommon – lymphangitis, skin necrosis.

Reproductive system disorders:
Common – spasmodic pain in the lower abdomen (in women).

Pregnancy, puerperium and perinatal conditions:
Uncommon – increased uterine tone, uterine ischemia.

Administration site conditions:
Uncommon – necrosis at injection site.

Shelf life. 3 years.

The reconstituted solution for injection should be used immediately.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Incompatibilities. Not known.

Packaging. 1 vial of powder with 1 ampoule of solvent (5 ml) in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Ferring GmbH, Germany.

Manufacturer's address and location of operations.
Wittland 11, 24109 Kiel, Germany.