Bleeding oesophageal varices.
The administration of terlipressin is for emergency treatment in cases of acute bleeding from oesophageal varices until endoscopic therapy is available. Afterwards, administration of terlipressin for the treatment of bleeding from oesophageal varices is usually an adjuvant therapy to the endoscopic stopping of bleeding. Terlipressin can also be used for reducing early secondary bleeding.

Hepatorenal syndrome
Emergency treatment of type 1 hepatorenal syndrome as defined by the ICA (international Club of Ascites) 2007 criteria, characterized by spontaneous acute renal insufficiency, in patients suffering from severe cirrhosis, with ascites.

Posology
Bleeding oesophageal varices.
Unless otherwise prescribed, initially 1-2 ampoules of GLYPRESSIN® 1mg/8.5ml Solution for Injection (0.85 to 1.7 mg terlipressin) are administered intravenously in adults. The maintenance dose is 1 ampoule of GLYPRESSIN® 1mg/8.5ml Solution for Injection after 4-6 hours. To adapt to the course of disease, the duration of treatment is to be reduced to 2-3 days.
The standard value for the maximum daily dose of GLYPRESSIN® 1mg/8.5ml Solution for Injection is 6 x 17 μg/kg body weight. For an adult person of 70 kg body weight, this corresponds to a dose of 8 to 9 ampoules (6.8-7.65 mg) per day, to be administered in 4-hour intervals.
Hepatorenal syndrome
Terlipressin is usually started at a dose of 1 ampoule of GLYPRESSIN® 1mg/8.5ml Solution for Injection (0.85 mg terlipressin) every 4 to 6 hours. The dose can be increased to a maximum of 2 ampoules of GLYPRESSIN® 1mg/8.5ml Solution for Injection (1.7 mg terlipressin) every 4 hours if serum creatinine does not decrease at least 25 % after 3 days of treatment.
Treatment is maintained until serum creatinine has decreased below 1,5 mg/dl (133 μmol/L). For patients with partial response (serum creatinine does not decrease < 133 μmol/L) or in those patients without reduction of serum creatinine, treatment should be discontinued within 14 days.
Recurrence after withdrawal of therapy is uncommon. Retreatment with terlipressin is generally
effective.
Clinical data indicates that adding human albumin 1g/kg body weight on the first day and afterwards in a dosage of 20 – 40 g/day may be more efficacious than treating with terlipressin alone in patients with hepatorenal syndrome. In most of the clinical studies examining the use of terlipressin for treatment of hepatorenal syndrome type 1, human albumin was administered simultaneously with these doses.
The standard average duration of treatment is 10 days. Maximum treatment duration should not exceed 14 days.

Method of administration:

GLYPRESSIN® 1mg/8.5ml Solution for Injection is slowly administered intravenously.
Elderly patients:GLYPRESSIN® 1mg/8.5ml Solution for Injection should be used with caution in patients over 70 years of age.
Paediatric population: GLYPRESSIN® 1mg/8.5ml Solution for Injection is not recommended in children and adolescents due to insufficient experience on safety and efficacy.
Renal insufficiency:GLYPRESSIN® 1mg/8.5ml Solution for Injection should only be used with caution in patients with chronic renal failure.
Hepatic insufficiency: A dose adjustment is not required in patients with liver failure.

GLYPRESSIN® 1mg/8.5ml Solution for Injection should be used with caution and under close monitoring in case of the following concomitant diseases:
- Septic shock;
- Bronchial asthma;
- Respiratory deficiencies;
- Uncontrolled hypertension;
- Cerebral, coronary or peripheral vascular diseases (e.g. advanced arteriosclerosis);
- Pre-existing seizures (convulsions);
- Cardiac arrhythmias;
- Cardiac diseases;
- Coronary insufficiency or previous myocardial infarction;
- Chronic renal insufficiency,
- Elderly patients over 70 years of age as experience is limited in this group.

Hypovolaemic patients also often show increased vasoconstriction and atypical cardiac reactions.
Due to the low antidiuretic effect of terlipressin (only approx. 3 % of the antidiuretic action of native vasopressin), attention should be drawn to possible hyponatraemia and hypokalaemia, especially in patients with already disturbed electrolyte balance.
During treatment regular controls of blood pressure, ECG/EKG, heart rate, serum levels of sodium and potassium, as well as fluid balance are required.
GLYPRESSIN® 1mg/8.5ml Solution for Injection is only to be used under continuous monitoring of the cardiovascular function using intensive medical units.
In case of emergency requiring immediate treatment before hospitalization, special attention is to be drawn to volume deficiency syndromes.
GLYPRESSIN® 1mg/8.5ml Solution for Injection has no effect on arterial bleeding.
To avoid local necrosis at the injection site, an intravenous injection should be administered.

Skin Necrosis:

During post-marketing experience several cases of cutaneous ischemia and necrosis unrelated to the injection site have been reported. Patients with peripheral venous hypertension or morbid obesity seem to have a greater tendency to this reaction. Therefore, extreme 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 arrhythmias 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, 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, electrolytic anormalities, concomitant medications that can prolong the QT interval, such as class IA and III antiarrhythmics, erythromycin, certain antihistamines and tricyclic antidepressants or medications that can cause hypokalaemia or hypomagnesemia (e.g. some diuretics).
Special populations:
Elderly:There is only limited experience in the treatment of elderly; therefore, terlipressin should only be used in this population with special care. There are no dose recommendations for elderly.
Due to lack of data and experience, GLYPRESSIN® 1mg/8.5ml Solution for Injection should not be used in children and adolescents.

8.5 ml of GLYPRESSIN® 1mg/8.5ml Solution for Injection contain 1.34 mmol (30.71 mg) sodium. This should be considered in patients receiving sodium-controlled diet (low sodium/low salt).

Terlipressin increases the hypotensive effect of non-selective β-blockers on the portal vein. The reduction in heart rate and cardiac output caused by the treatment can be attributed to the inhibition of the reflexogenic activity of the heart through the vagus nerve as a result of increased blood pressure. Concomitant treatment with drugs known to induce bradycardia (e.g. propofol, sufentanil) can cause severe bradycardia.
Terlipressin can trigger ventricular arrhythmias including "Torsade de pointes". 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).

Pregnancy
GLYPRESSIN® 1mg/8.5ml Solution for Injection is contraindicated during pregnancy. GLYPRESSIN® 1mg/8.5ml Solution for Injection causes uterine contractions and increased intrauterine pressure during early pregnancy and may reduce uterine blood flow.
GLYPRESSIN® 1mg/8.5ml Solution for Injection may have a harmful effect on pregnancy and the health of the foetus. Rabbits showed spontaneous abortions and malformations following treatment with GLYPRESSIN® 1mg/8.5ml Solution for Injection.
Lactation: 

It is not known whether terlipressin passes into 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.

No studies on the effects on ability to drive and use machines have been performed.

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

Metabolism and nutrition disorders:
Common (>=1/100 to <1/10): hyponatraemia
Nervous system disorders:
Common (>=1/100 to <1/10) headache.
Uncommon (>=1/1,000 to <1/100): causing of seizure disorders.
Very rare (<1/10,000): apoplexy
Cardiac disorders:
Common (>=1/100 to <1/10): bradycardia, ventricular and supraventricular arrhythmia, signs of ischaemia in ECG/EKG,
Uncommon (>=1/1,000 to <1/100): acute hypertension rises in particular in patients already suffering from hypertension (generally, it decreases spontaneously), tachycardia, atrial fibrillation, ventricular extrasystoles, angina pectoris, myocardial infarction, overload of liquid with pulmonary oedema, torsade de pointes, cardiac insufficiency.
Very rare (<1/10,000) myocardial ischemia
Vascular disorders:
Common (>=1/100 to <1/10) peripheral vasoconstriction, peripheral ischaemia, hypertension, pallor of skin, hypo-tension
Uncommon (>=1/1,000 to <1/100): intestinal ischaemia, peripheral cyanosis, hot flushes
Respiratory, thoracic and mediastinal disorders:
Uncommon (>=1/1,000 to <1/100): difficulty in breathing, painful breathing, pain in the chest (thoracic pain), bronchial spasm, respiratory insufficiency, cessation of breathing,
Rare (>=1/10,000 to <1/1,000): dyspnoea
Gastrointestinal disorders:
Common (>=1/100 to <1/10): spasmodic abdominal pain, nausea, diarrhoea.
Uncommon (>=1/1,000 to <1/100): vomiting
Skin and subcutaneous tissue disorders:
Common (>=1/100 to <1/10): paleness.
Uncommon (>=1/1,000 to <1/100): lymphangitis, skin necrosis
Pregnancy, puerperium and perinatal conditions:
Uncommon (>=1/1,000 to <1/100): Uterine hypertonus, Uterine ischemia
General disorders and administration site conditions:
Uncommon (>=1/1,000 to <1/100): necrosis at injection site
Reproductive system and breast disorders:
Common (>=1/100 to <1/10): spasmodic pain in the lower abdomen (in women)During post-marketing experience, several cases of QT interval prolongation and ventricular arrhythmias including "Torsade de pointes" have been reported and several cases of cutaneous ischemia and necrosis unrelated to the injection site have been reported.

The recommended dose (1.7 mg/4 hours) should not be exceeded as the risk of severe circulatory disorders increases with the dose. Increased blood pressure in patients with known hypertension can be controlled with 150 μg clonidine IV. Bradycardia requiring therapy should be treated with atropine.

Pharmacotherapeutic group: systemic hormonal preparations, posterior pituitary hormones, vasopressin and analogues
ATC code: H01BA04
Terlipressin possesses little pharmacological activity, however, it is metabolized into the active lysine vasopressin by enzymatic hydrolysis. Doses of 0.85 mg and 1.7 mg lower the portal pressure and cause marked vasoconstriction. The lowering of the portal pressure and the reduction in the blood flow of the azygous vein are dose-dependent. The effect of the lower dose decreased after 3 hours, while haemodynamic data show that terlipressin 1.7 mg is more effective than 0.85 mg as the higher dose has a more reliable effect over the entire period of treatment (4 hours).

Terlipressin reduces the portal hypertension, simultaneously reducing the circulation in the portal vascular zone and contracting the unstriated oesophageal muscles under consecutive compression of the oesophageal varices.

The bioactive lysine vasopressin (LVP) is released protracted from the inactive hormonogen terlipressin and remains in a concentration range above the minimum effective and below the toxic concentration over a period of 4 - 6 hours due to the metabolic elimination of the LVP that is in parallel to the release. The specific actions of terlipressin are to be evaluated as follows:
Gastrointestinal system:

Terlipressin increases the tonus of vasal and extravasal unstriated muscle cells. Due to the increased resistance of the terminal arterial vessels, there is a decreased circulation of the splanchnic nerve. Reduction of the arterial flow leads to a pressure decrease in the portal circulation. The simultaneous contraction of the intestinal muscles leads to an increased peristalsis. Furthermore, it could be shown that the muscles of the oesophageal wall are contracting and thus “ligate” varices experimentally created.

Kidney:

Terlipressin has only 3 % of the antidiuretic action of native vasopressin. This reactivity is not clinically relevant. Renal circulation is not significantly changed in normovolaemic condition. In hypovolaemic condition, renal circulation is increased.

Blood pressure:

The use of terlipressin has a slow haemodynamic effect over 2 - 4 hours. The blood pressure is slightly increased systolically and diastolically. In case of renal hypertonia and general vascular sclerosis, stronger blood pressure increases were observed.

Heart:

No cardiotoxic effects, even with the highest dosage, have been determined under terlipressin. Influences on the heart, such as bradycardia, arrhythmia, coronary insufficiency, occur possibly because of reflex or direct vascular constrictive effects of terlipressin.

Uterus:

Under terlipressin, blood circulation of the myometrium and endometrium is strongly decreased.

Skin:

Due to its vasoconstricting effect, terlipressin leads to an insufficient blood circulation of the skin. All authors report a clearly visible paleness of body and skin in their patients.

The haemodynamic effect and the effect on the unstriated muscle cells are the main factors in the pharmacology of terlipressin. The centralizing effect in hypovolaemic condition is a desired side effect in patients with bleeding oesophageal varices.

The mean plasma half-life of terlipressin is 24 + 2 minutes. After an IV bolus injection, terlipressin is eliminated according to a 2nd order kinetics. For the distribution phase (up to 40 minutes), a plasma half-life of 12 minutes has been determined. By setting free singular rest-glycyl, the hormone lysine-vasopressine is slowly released and reaches its peak concentration after 120 minutes. Only 1 % of the injected terlipressin can be detected in the urine. This indicates a nearly complete degradation by endo- and exo-peptidases of the liver and the kidney.

Preclinical data reveal no hazard for humans based on conventional studies of single-and multiple dose toxicity as well as genotoxicity. No carcinogenicity studies have been performed with terlipressin. At doses relevant to humans, the only effects observed in animals were those attributed to the pharmacological activity of terlipressin. There are no pharmacokinetic data from animal models available which would allow comparison with human plasma concentrations. However, as administration is done by the intravenous route, substantial systemic exposition can be assumed.
An embryo-foetal study in rats showed no side effects of terlipressin. In rabbits, however,
abortions occurred that were probably related to maternal toxicity. Furthermore, a small
number of foetuses showed ossification anomalies and a single case of cleft palate was observed.

Sodium chloride, acetic acid 99 %, sodium acetate 3 H2O, water for injection.

Incompatibilities are unknown at present.

Store in refrigerator (2 °C – 8 °C). Keep ampoules in the outer carton, in order to protect from light.

Colorless glass ampoule.
Pack size: OP with 5 ampoules with 8.5 ml solution each

Any unused product or waste material should be disposed of in accordance with national requirements.