Glypressin 1 mg Powder and Solvent for Solution for Injection

Section 2 - Addition of 'excipients with known effect' subsection

Section 4.2 - Addition of 'Special Populations' and 'Method of Administration' subsections

Section 4.3 - Minor typographical update

Section 4.4 - Addition of information on Cardiac, pulmonary and vascular disease, Torsade de pointes, Paediatric populations and elderly patients and Excipients

Section 4.5 - Addition of paragraph on concomitant medications that can prolong the QT interval 

Section 4.8 - Adverse Events updated in accordance with current MedDRA terminology 

Section 4.9 - Minor typographical update

Section 5.1 - Update information on pharmacodynamic properties

Section 2 - update of information on the ampoule and vial.

1.         NAME OF THE MEDICINAL PRODUCT

Glypressin 1 mg Powder and Solvent for Solution for Injection

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule contains terlipressin acetate 1 mg.

Excipient: Each 5 ml vial of solvent contains 17.7 mg sodium.

For full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

White, sterile powder. 

Clear, colourless solvent.

4.         CLINICAL PARTICULARS

4.1       Therapeutic Indications

For use in the short term management of bleeding oesophageal varices.

“Emergency treatment of type 1 hepatorenal syndrome, as defined by IAC (internationalInternational Ascites Club) criteria”.

4.2       Posology and method of administration

1) Short term management of bleeding oesophageal varices

Adults:
Initially an i.v. 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 terlipressin acetate i.v. every 4 hours in patients with body weight < 50 kg or if adverse effects occur.

2) In type 1 hepatorenal syndrome

3 to 4 mg 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.

In 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

4.3       Contraindications

Hypersensitivity to terlipressin or any other excipient of the product.

Contraindicated in pregnancy.

4.4       Special warnings and precautions for use

Blood pressure, heart rate and fluid balance should be monitored during treatment.

Caution should be exercised in treating patients with hypertension, recognised heart disease, renal dysfunction, cerebral or peripheral vascular disease, asthma or respiratory failure.

To avoid local necrosis at the injection site, the injection must be administered intravenously.

In patients with septic shock with a low cardiac output terlipressin should not be used.

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.

Children and the elderly: 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.

4.5              Interaction with other medicinal products and other forms of interactionsinteraction

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 the cardiac activity via the vagus nerve due to the elevated blood pressure. 

4.6       PregnancyFertility, pregnancy and lactation

Treatment with GLYPRESSIN during pregnancy is contraindicated (see sections 4.3 and 5.3).  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.

Information on transfer of GLYPRESSIN to breast milk is insufficient.  GLYPRESSIN should not be used in breast feeding women.

4.7       Effects on ability to drive and use machines

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

4.8       Undesirable effects

The most commonly reported undesired effects in clinical trials (frequency 1-10%) are paleness, increased blood pressure, abdominal pain, nausea, diarrhoea, and headache. 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

4.9       Overdose

The recommended dose (2 mg/4 hours) should not be exceeded as the risk of severe circulatory adverse effects is dose-dependent.

Elevated blood pressure in patients with hypertension can be controlled with clonidine 150 µg iv.  Severe bradycardia should be treated with atropine.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Posterior pituitary lobe hormones (vasopressin and analogues)

ATC code: H01B A04

Glypressin may be regarded as a circulating depot of lysine vasopressin.  Following i.v. injection, three glycyl moieties are enzymatically cleaved from the N terminal to release lysine vasopressin.

The slowly released vasopressin reduces blood flow in the splanchnic circulation in a prolonged manner, thereby helping to control bleeding from ruptured oesophageal varices.

5.2       Pharmacokinetic properties

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 (T 1/2α) is about 8-10 minutes.  The half-life of elimination (T ½ 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.

5.3       Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of excipients

Powder for solution for injection (vial):)

Mannitol

Hydrochloric acid (for pH-adjustment)

Solvent (ampoule):)

Sodium chloride

Hydrochloric acid (for pH-adjustment).

Water for injections

6.2       Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3       Shelf life

Unopened:3 years.

6.4       Special precautions for storage

Do not store above 25°C.  Store in the original package in order to protect from light.

The reconstituted solution must be used immediately after reconstitution.

6.5       Nature and contents of container

Type I glass vial with bromobutyl rubber stopper and type I glass ampoule.

The vial contains terlipressin acetate 1 mg.  The ampoule has a coloured dot indicating the cut area and contains 5 ml of clear, colourless solvent.

Pack size:  5 sets of 1 vial + 1 ampoule.

6.6       Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Reconstitute Glypressin with the solvent provided immediately prior to use.  For single use only. Discard any unused solution.

7.     MARKETING AUTHORISATION HOLDER

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

8.     MARKETING AUTHORISATION NUMBER

1.         NAME OF THE MEDICINAL PRODUCT

Glypressin 1 mg Powder and Solvent for Solution for Injection

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule contains terlipressin acetate 1 mg.

Excipient: Each 5 ml vial of solvent contains 17.7 mg sodium.

For full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

White, sterile powder. 

Clear, colourless solvent.

4.         CLINICAL PARTICULARS

4.1       Therapeutic Indications

For use in the short term management of bleeding oesophageal varices.

“Emergency treatment of type 1 hepatorenal syndrome, as defined by IAC (internationalInternational Ascites Club) criteria”.

4.2       Posology and method of administration

1) Short term management of bleeding oesophageal varices

Adults:
Initially an i.v. 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 terlipressin acetate i.v. every 4 hours in patients with body weight < 50 kg or if adverse effects occur.

2) In type 1 hepatorenal syndrome

3 to 4 mg 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.

In 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

4.3       Contraindications

Hypersensitivity to terlipressin or any other excipient of the product.

Contraindicated in pregnancy.

4.4       Special warnings and precautions for use

Blood pressure, heart rate and fluid balance should be monitored during treatment.

Caution should be exercised in treating patients with hypertension, recognised heart disease, renal dysfunction, cerebral or peripheral vascular disease, asthma or respiratory failure.

To avoid local necrosis at the injection site, the injection must be administered intravenously.

In patients with septic shock with a low cardiac output terlipressin should not be used.

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.

Children and the elderly: 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.

4.5              Interaction with other medicinal products and other forms of interactionsinteraction

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 the cardiac activity via the vagus nerve due to the elevated blood pressure. 

4.6       PregnancyFertility, pregnancy and lactation

Treatment with GLYPRESSIN during pregnancy is contraindicated (see sections 4.3 and 5.3).  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.

Information on transfer of GLYPRESSIN to breast milk is insufficient.  GLYPRESSIN should not be used in breast feeding women.

4.7       Effects on ability to drive and use machines

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

4.8       Undesirable effects

The most commonly reported undesired effects in clinical trials (frequency 1-10%) are paleness, increased blood pressure, abdominal pain, nausea, diarrhoea, and headache. 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;  Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

4.9       Overdose

The recommended dose (2 mg/4 hours) should not be exceeded as the risk of severe circulatory adverse effects is dose-dependent.

Elevated blood pressure in patients with hypertension can be controlled with clonidine 150 µg iv.  Severe bradycardia should be treated with atropine.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Posterior pituitary lobe hormones (vasopressin and analogues)

ATC code: H01B A04

Glypressin may be regarded as a circulating depot of lysine vasopressin.  Following i.v. injection, three glycyl moieties are enzymatically cleaved from the N terminal to release lysine vasopressin.

The slowly released vasopressin reduces blood flow in the splanchnic circulation in a prolonged manner, thereby helping to control bleeding from ruptured oesophageal varices.

5.2       Pharmacokinetic properties

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 (T 1/2α) is about 8-10 minutes.  The half-life of elimination (T ½ 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.

5.3       Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of excipients

Powder for solution for injection (vial):)

Mannitol

Hydrochloric acid (for pH-adjustment)

Solvent (ampoule):)

Sodium chloride

Hydrochloric acid (for pH-adjustment).

Water for injections

6.2       Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3       Shelf life

Unopened:3 years.

6.4       Special precautions for storage

Do not store above 25°C.  Store in the original package in order to protect from light.

The reconstituted solution must be used immediately after reconstitution.

6.5       Nature and contents of container

Type I glass vial with bromobutyl rubber stopper and type I glass ampoule.

The vial contains terlipressin acetate 1 mg.  The ampoule has a coloured dot indicating the cut area and contains 5 ml of clear, colourless solvent.

Pack size:  5 sets of 1 vial + 1 ampoule.

6.6       Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Reconstitute Glypressin with the solvent provided immediately prior to use.  For single use only. Discard any unused solution.

7.     MARKETING AUTHORISATION HOLDER

Ferring Ireland Ltd

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

8.     MARKETING AUTHORISATION NUMBER

Variarion approved to change section 4.4 of SPC

Variarion approved to change section 4.4 of SPC