Glypressin

Powder (vial): White lyophilized powder.
Solvent (ampoule): Clear, colourless liquid.
Powder: One vial contains 1 mg terlipressin acetate, corresponding to 0.86 mg terlipressin.
The concentration of the reconstituted solution is 0.2 mg terlipressin acetate/mL.
Excipients with known effect: One vial contains 0.77 mmol (17.7 mg) sodium.
Excipients/Inactive Ingredients: Powder: Mannitol (E 421), Hydrochloric acid.
Solvent: Sodium chloride, Hydrochloric acid, and Water for injections.

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 is more effective than 1 mg with a sustained effect throughout the treatment period of 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 (42). Seventy-eight patients with type 1 hepatorenal syndrome were randomly assigned to either continuous IV infusion 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: The pharmacokinetics of terlipressin follows a two-compartment model with a rapid distribution phase.
Absorption: Terlipressin is administered by the intravenous route resulting in instant systemic exposure, requiring no absorption.
Distribution: In patients with liver cirrhosis with or without hepatorenal syndrome the distribution volume is in the range between 0.2 and 0.5 l/kg.
Biotransformation: The concentration of the active metabolite, lysine-vasopressin starts to increase approximately 30 minutes after bolus administration of terlipressin and peak levels are reached between 60 and 120 minutes after administration of terlipressin.
Elimination: The elimination half-life of terlipressin is approximately 40 minutes in patients with liver cirrhosis with and without hepatorenal syndrome and the reported clearance is in the range between 5 and 9 ml/kg/min.
Linearity: Terlipressin demonstrated a dose-dependent and approximate proportional increase in total exposure (AUC) after single IV injections to healthy subjects (n=2-14 subjects per dose group) in a dose range between 5 and 30 μg/kg.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of single-and repeat-dose toxicity, and genotoxicity. At dosages relevant to humans, the only effects observed in animals were those attributable to the pharmacological activity of terlipressin.
No pharmacokinetic data are available from animals, but as the route of administration was intravenous, systemic exposure as multiples of the maximum human dosages can be assumed for the animal studies.
An embryo-fetal study in rats demonstrated no adverse effects of terlipressin, but in rabbits abortions occurred, probably related to maternal toxicity, and there were ossification anomalies in a small number of fetuses and a single isolated case of cleft palate.
In a rat fertility study, mating of terlipressin-treated males with untreated females had no effect on the number of matings and frequency of insemination but led to decreased post-natal litter size. Testicular atrophy and disturbances of spermiogenesis observed in male rats treated with terlipressin for 3 weeks could not be confirmed. Likewise no testicular effects were seen in any other repeat-dose toxicity study in rats and dogs.
No carcinogenicity studies have been performed with terlipressin.

Treatment of bleeding oesophageal varices.
Treatment of type 1 hepatorenal syndrome, characterised by spontaneous acute renal insufficiency, in patients suffering from severe cirrhosis with ascites.

Posology: Bleeding oesophageal varices: Adults: Initially an IV injection of 2 mg 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 IV every 4 hours in patients with body weight <50 kg or if adverse effects occur. Consensus statement from the sixth Baveno Congress recommends up to 5 days.
Type 1 hepatorenal syndrome: 3 to 4 mg of 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 terlipressin treatment is advised. In other cases, terlipressin acetate 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: 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).
Elderly: 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.
Method of Administration: IV Injection.

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 recognized hypertension can be controlled with 150 mcg clonidine IV.
Bradycardia requiring treatment should be treated with atropine.

Contraindicated in pregnancy.
Hypersensitivity to the active substance or to any of the excipients of the product.

Warnings and precautions applicable to type 1 hepatorenal syndrome: Prior to treatment of type 1 hepatorenal syndrome, other types of acute kidney injury should be ruled out.
Renal impairment: Terlipressin should be avoided in patients with advanced renal dysfunction, i.e., baseline serum creatinine ≥442 μmol/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. Causal association to terlipressin has not been established. Patients should be monitored daily for any signs or symptoms suggestive of infection.
Warnings and precautions applicable to 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 ischaemia and pulmonary vascular congestion.
Patients with 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 given IV.
Skin necrosis: During post-marketing experience with terlipressin several cases of cutaneous ischaemia and necrosis unrelated to the injection site have been reported (see Adverse Reactions). Patients with diabetes mellitus and obesity seem to have a greater tendency to this reaction. Therefore, caution should be exercised when administering terlipressin in these patients.
Torsade de pointes: During clinical trials and post marketing experience, several cases of QT interval prolongation and ventricular arrythmias including "Torsade de pointes" have been reported. In most cases, patients had predisposing factors such as basal prolongation of the QT interval, electrolyte abnormalities (hypokalemia, hypomagnemesia) 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 prolong QT interval.
Children and the elderly: Particular caution should be exercised in the treatment of children and elderly patients, as experience is limited in these groups.
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 terlipressin during pregnancy is contraindicated (refer to Contraindications).
Terlipressin has been shown to cause uterine contractions and increased intrauterine pressure in early pregnancy and may decrease uterine blood flow. Terlipressin may have harmful effects on pregnancy and foetus.
Spontaneous abortion and malformation have been shown in rabbits after treatment with terlipressin.
Breastfeeding: It is not known whether terlipressin is excreted in human breast milk. The excretion of terlipressin 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 terlipressin should be made taking into account the benefit of breast-feeding to the child and the benefit of terlipressin therapy to the woman.
Fertility: No human data on the effects of terlipressin on fertility is available. Animal studies do not indicate harmful effects of terlipressin on male infertility.

The most commonly reported undesirable effects in clinical trials (frequency 1-10%) are paleness, increased blood pressure, abdominal pain, nausea, diarrhea, and headache. The antidiuretic effect of terlipressin may cause hyponatraemia unless the fluid balance is controlled.
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

The hypotensive effect of non-selective beta-blockers on the portal vein is increased with terlipressin.
Concomitant treatment with medicinal products with a known bradycardic effect (e.g. propofol, sufentanil) may lower the heart rate and cardiac output. These effects are due to the 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 QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that may cause hypokalemia or hypomagnemesia (e.g. some diuretics).

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special Precautions for Disposal and Other Handling: Mix solvent with powder for injection via the rubber stopper in the vial. The clear reconstituted solution must be injected IV immediately after reconstitution.
Any unused drug or waste materials should be disposed of in accordance with local requirements.

Do not store above 25°C. Store in the original package in order to protect from light.
Shelf-life: 3 years.

Haemostatics

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

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