Glypressin

Clear, colourless aqueous fluid.
8.5 ml of injection solution contains 1 mg terlipressin acetate (0.12 mg/ml).
Excipients with known effect: One ampoule contains 30.7 mg sodium.
Excipients/Inactive Ingredients: Sodium chloride, acetic acid, sodium acetate and water for injection.

Pharmacotherapeutic group: Posterior pituitary lobe hormones (vasopressin and analogues). ATC code: H01B A04.
Pharmacology: Pharmacodynamics: Terlipressin (Triglycyl-Lysine-Vasopressin) is a synthetic analogue of the natural posterior pituitary hormone vasopressin. Terlipressin is a pro-drug with partial, intrinsic activity by itself. Terlipressin is transformed into the fully active metabolite lysine-vasopressin (LVP) by enzymatic cleavage. LVP remains within the therapeutic concentration range over a period of 4-6 hours.
Doses of 1 and 2 mg terlipressin acetate effectively reduce the portal venous pressure and produce marked vasoconstriction. The lowering of portal pressure and azygos blood flow is dependent on dose. The effect of the low dose is reduced after 3 hours, while haemodynamic data show that 2 mg terlipressin acetate is more effective than 1 mg terlipressin acetate with a sustained effect throughout the treatment period (4 to 6 hours).
Clinical efficacy and safety: Continuous IV infusion versus IV boluses in the treatment of type 1 hepatorenal syndrome in patients with cirrhosis.
The safety of continuous IV infusion of terlipressin has been compared with IV bolus in an open-label randomised controlled multicentre trial. Seventy-eight patients with type 1 hepatorenal syndrome were randomly assigned to either continuous IV infusion of terlipressin acetate at the initial dose of 2 mg/day or IV boluses of terlipressin at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups. The primary endpoint was defined as the prevalence of treatment-related adverse events (AEs) between the two groups. Both the total rate of treatment-related AEs as well as severe treatment-related AEs were lower in the continuous infusion group than in the bolus group (all treatment-related AEs: 12/34 patients (35%) vs 23/37 patients (62%), p<0.025. Severe treatment-related AEs: 7/34 patients (21%) vs 16/37 patients (43%); p<0.05). The rate of response to terlipressin was not statistically significantly different between the continuous infusion and bolus groups (76% vs 65%). The probability of 90-day transplant-free survival was not significantly different between the continuous infusion group and the bolus group (53% vs 69%).
Pharmacokinetics: GLYPRESSIN is administered by bolus i.v. injection. It shows a biphasic plasma level curve which indicates that a two compartment model can be applied. The half-life of distribution (T½_α) is about 8-10 minutes. The half-life of elimination (T½_β) is about 50-70 minutes.
Lysine vasopressin reaches maximum plasma levels about 1-2 hours following i.v. administration and has a duration of activity of 4-6 hours.
Toxicology: Preclinical Safety Data: There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections.

Bleeding oesophageal varices.
Emergency treatment of type 1 hepatorenal syndrome, as defined by IAC (International Ascites Club) criteria.

Posology: Bleeding oesophageal varices: Adults: Initially an i.v. injection of 2 mg (2 x 8.5 ml) terlipressin acetate is given every 4 hours. The treatment should be maintained until bleeding has been controlled for 24 hours, but up to a maximum of 48 hours. After the initial dose, the dose can be adjusted to 1 mg (8.5 ml) terlipressin acetate i.v. every 4 hours in patients with body weight <50 kg or if adverse effects occur.
Type 1 hepatorenal syndrome: An i.v. injection 3 to 4 mg (3 x 8.5 ml to 4 x 8.5 ml) terlipressin acetate every 24 hours as 3 or 4 administrations. In the absence of any reduction of the serum creatinine after 3 days of treatment, cessation of GLYPRESSIN treatment is advised. As an alternative to bolus injection, terlipressin can be administered as a continuous intravenous (IV) infusion with a starting dose of 2 mg of terlipressin acetate/24 hours and increased to a maximum of 12 mg of terlipressin acetate/24 hours. Administration of terlipressin as continuous IV infusion may be associated with lower rates of severe adverse events than with administration by IV bolus (see Pharmacology: Pharmacodynamics under Actions).
In the other cases, GLYPRESSIN treatment is to be pursued until the obtaining either of a serum creatinine less than 130 µmol/litre or of a drop of at least 30% in the serum creatinine with respect to the value measured at the time of diagnosis of hepatorenal syndrome.
The standard average duration of treatment is 10 days.
Special Populations: Elderly patients: There is no data available regarding dosage recommendation in the elderly.
Paediatric population: There is no data available regarding dosage recommendation in the paediatric population.
Type 1 hepatorenal syndrome: Renal impairment: Terlipressin should be avoided in patients with advanced renal dysfunction, i.e., baseline serum creatinine ≥442 µmol/L (5.0 mg/dL), unless the benefit is judged to outweigh the risks (see Precautions).
Hepatic impairment: Terlipressin should be avoided in patients with severe liver disease defined as Acute-on-Chronic Liver Failure (ACLF) grade 3 and/or a Model for End-stage Liver Disease (MELD) score ≥39, unless the benefit is judged to outweigh the risks (see Precautions).
Method of Administration: IV injection.
Type 1 hepatorenal syndrome: IV injection or IV infusion.

The recommended dose in the specific patient population should not be exceeded as the risk of severe circulatory adverse effects is dose-dependent.
Elevated blood pressure in patients with recognised hypertension can be controlled with 150 mcg clonidine i.v. Bradycardia requiring treatment should be treated with atropine.

Hypersensitivity to the active substance or to any other excipients listed in Description. Contraindicated in pregnancy.

Type 1 hepatorenal syndrome: Prior to use of terlipressin for hepatorenal syndrome, it must be ascertained that the patient has an acute functional renal failure and this functional renal failure does not respond to a suitable plasma expansion therapy.
Renal impairment: Terlipressin should be avoided in patients with advanced renal dysfunction, i.e., baseline serum creatinine ≥442µmol/L (5.0 mg/dL), when treated with terlipressin for type 1 hepatorenal syndrome, unless the benefit is judged to outweigh the risks. Reduced efficacy in reversal of hepatorenal syndrome, increased risk of adverse events, and increased mortality in this patient group have been observed in clinical trials (see Dosage & Administration).
Hepatic impairment: Terlipressin should be avoided in patients with severe liver disease defined as Acute-on-Chronic Liver Failure (ACLF) grade 3 and/or a Model for End-stage Liver Disease (MELD) score ≥39, when treated with terlipressin for type 1 hepatorenal syndrome, unless the benefit is judged to outweigh the risks. Reduced efficacy in reversal of hepatorenal syndrome, increased risk of respiratory failure, and increased mortality in this patient group have been observed in clinical trials (see Dosage & Administration).
Respiratory events: Fatal cases of respiratory failure, including respiratory failure due to fluid overload, have been reported in patients treated with terlipressin for type 1 hepatorenal syndrome.
Patients with a new onset of breathing difficulties or worsening of respiratory disease should be stabilised prior to receiving their first dose of terlipressin.
Caution should be exercised when terlipressin is administered together with human albumin as part of the standard of care for type 1 hepatorenal syndrome. In case of signs or symptoms of respiratory failure or fluid overload, dose reduction of human albumin should be considered. If respiratory symptoms are severe or do not resolve, treatment with terlipressin should be discontinued.
Sepsis/septic shock: Cases of sepsis/septic shock, including fatal cases, have been reported in patients treated with terlipressin for type 1 hepatorenal syndrome. Patients should be monitored daily for any signs or symptoms suggestive of infection.
All indications: Monitoring during treatment: During treatment, regular monitoring of blood pressure, ECG, or heart rate, oxygen saturation, serum levels of sodium and potassium, as well as fluid balance are required.
Particular care is required in management of patients with cardiovascular or pulmonary disease since terlipressin may induce ischemia and pulmonary vascular congestion.
Caution should be exercised in treating patients with hypertension, recognised heart disease, renal dysfunction, cerebral or peripheral vascular disease, asthma or respiratory failure.
Septic shock: In patients with septic shock with a low cardiac output terlipressin should not be used.
Injection site reaction: To avoid local necrosis at the injection site, the injection must be administered intravenously.
Torsade de pointes: During clinical trials and post-marketing experience, several cases of QT interval prolongation and ventricular arrhythmias including "Torsade de pointes" have been reported (see Adverse Reactions). In most cases, patients had predisposing factors such as basal prolongation of the QT interval, electrolyte abnormalities (hypokalemia, hypomagnesemia) or medications with concomitant effect on QT prolongation. Therefore, extreme caution should be exercised in the use of terlipressin in patients with a history of QT interval prolongation, electrolyte abnormalities, or concomitant medications that can prolong the QT interval (see Interactions).
Paediatric population and elderly patients: Particular caution should be exercised in the treatment of children and elderly patients, as experience is limited in these groups.
There is no data available regarding dosage recommendation in these special patient categories.
Excipients: This medicinal product contains 1.33 mmol (or 30.7 mg) of sodium per ampoule, equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.

Pregnancy: Treatment with GLYPRESSIN during pregnancy is contraindicated (see Contraindications and Pharmacology: Toxicology: Preclinical Safety Data under Actions). GLYPRESSIN has been shown to cause uterine contractions and increased intrauterine pressure in early pregnancy and may decrease the uterine blood flow. GLYPRESSIN may have harmful effects on pregnancy and foetus.
Spontaneous abortion and malformation of the foetus have been shown in rabbits after treatment with GLYPRESSIN.
Breast-feeding: It is not known whether GLYPRESSIN is excreted in human breast milk. The excretion of GLYPRESSIN in milk has not been studied in animals. A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with GLYPRESSIN should be made taking into account the benefit of breast-feeding to the child and the benefit of GLYPRESSIN therapy to the woman.

The most commonly reported undesired effects in clinical trials are paleness, increased blood pressure, abdominal pain, nausea, diarrhoea and headache.
Tabulated list of adverse reactions: There are adverse reactions that appear twice in the table, as the estimated frequencies differ between indications. (See table.)

Click on icon to see table/diagram/image

Safety related to method of administration: Based on results from a dedicated randomised controlled multicentre trial, administration of terlipressin as continuous IV infusion may be associated with lower rates of severe adverse events than with administration by IV bolus (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).

The hypotensive effect of non-selective beta-blockers on the portal vein is increased with terlipressin. Concomitant treatment with medicinal products with a known bradycardiac effect (e.g. propofol, sufentanil) may lower the heart rate and cardiac output. These effects are due to reflexogenic inhibition of cardiac activity via the vagus nerve due to the elevated blood pressure.
Terlipressin can trigger "torsade de pointes" (see Precautions and Adverse Reactions). Therefore, extreme caution should be exercised in the use of terlipressin in patients with concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that may cause hypokalaemia or hypomagnesemia (e.g. some diuretics).

Special Precautions for Disposal and Other Handling: Each ampoule is for single use only. Discard any unused solution.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2°C-8°C). The ampoules are stored in the outer carton in order to protect from light.
Shelf Life: 2 years.

Haemostatics

H01BA04 - terlipressin ; Belongs to the class of vasopressin and analogues. Used in posterior pituitary lobe hormone preparations.

P₁S₁S₃