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.

Posology
Unless otherwise prescribed, initially 1‑2 ampoule 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.
Method of administration
GLYPRESSIN® 1mg/8.5ml Solution for Injection is slowly administered
intravenously. The duration of administration is 2‑3 days.
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.

shock in patients with low cardiac output.
-    Pregnancy.
Special Warnings and Precautions for Use
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 blood pressure, heart rate and ECG/EKG as well as
fluid balance should be observed.
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).

GLYPRESSIN fails under X of pregnancy categories
Pregnancy: GLYPRESSIN is contraindicated during pregnancy.
GLYPRESSIN causes uterine contractions and increased intrauterine pressure during early pregnancy
and may reduce uterine blood flow. GLYPRESSIN may have a harmful effect on pregnancy and the
health of the foetus. Rabbits showed spontaneous abortions and malformations following treatment
with GLYPRESSIN.
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.
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 rise, 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, hypotension.
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): dyspnea.
Gastrointestinal disorders
Common (>1/100 to <1/10): spasmodic abdominal pain, nausea, diarrhea.
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 does 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 i.v.. 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 i.v.
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 restglycyl,
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.

N/A

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.