Glypressin 1 mg/ 8.5 ml 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 4.4 - 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 9: new text, "Date of last renewal: 25th September 2014"

Section 10: revision of text updated to February 2016

Section 9: new text, "Date of last renewal: 25th September 2014"

Section 10: revision of text updated to February 2016

Update to include new HPRA contact information

Update to include new HPRA contact information

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Glypressin  1 mg/ 8.5 ml solution for injection

2.         Qualitative And Quantitative Composition 

8.5 ml of injection solution contains 1 mg1mg Terlipressin Acetate (0.12 mg/ml) and 1.33 mmol of sodium.

                   

For a full list of excipients see section 6.1.

3.         Pharmaceutical Form

Solution for injection.

Clear, colourless aqueous fluid.

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 (iInternational 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 (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.

2)  In type 1 hepatorenal syndrome:

An i.v. injection 3 to 4 mg (3x8.5ml to 4x8.5ml) 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. 

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 medicamentsmedicinal products and other forms of interaction

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 reflexofenic inhibition of the cardiac activity via the vagus nerve due to 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 any transfer of Glypressin to breast milk is insufficient.  Glypressin should not be used in breast feeding women.

Lactation

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.

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.

MedDRA System Organ Class	COMMON	UNCOMMON	RARE	Not known
Disorder	(10-1%)	(1-0.1%)	(0.1-0.01%)	(cannot be estimated from the available data)
Metabolism and nutrition disorders		Hyponatraemia if fluid not monitored
Nervous system disorders	Headache
Cardiac disorders	Bradycardia	Atrial Fibrillation		Torsade de pointes
		Ventricular Extracystoles		Cardiac failure
		Tachycardia
		Chest pain
		Myocardial Infarction
		Fluid overload with pulmonary oedema Torsades de pointe Cardiac failure
Vascular disorders	Peripheral vasoconstriction	Intestinal ischaemia
	Peripheral ischemia	Peripheral cyanosis
	Facial pallor	Hot flushes
	Hypertension
Respiratory, thoracic and mediastinal disorders		Respiratory distress	Dyspnoea
		Respiratory failure
Gastrointestinal disorders	Transient abdominal cramps	Transient nausea
	Transient diarrhoea	Transient vomiting
Skin and subcutaneous tissue disorders				Skin necrosis
Pregnancy, puerperium and perinatal conditions				Uterine constriction Decreased uterine blood flowUterine ischemia
General disorders and administration site disorders		Injection site necrosis

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 mg2mg terlipressin acetate/4 hours) 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.

5.         Pharmacological Properties

5.1       Pharmacodynamic properties

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

ATC code: H01B A04

 

Terlipressin initially has an effect of its own, but is converted by enzymatic cleavage to lysine vasopressin. 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 as the higher dose produces a dependable effect throughout the period of treatment (4 hours)

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 (T1/2a)) is about 8-10 minutes.

The half-life of elimination (T1/2b)) 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         

Sodium chloride

Acetic acid

Sodium acetate

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

2 years            

6.4       Special precautions for storage

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

6.5      Nature and contents of container

Each carton contains five clear hydrolytic class 1 glass ampoules, 10ml nominal volume. 

The ampoule has a coloured dot indicating the cut area. It contains 8.5ml of solution for injection.  

6.6       Instructions for use / handling

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

Each ampoule is 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

            PA 1009/4/2

9.         Date Of First Authorisation / Renewal Of Authorisation

            25^th September 2009

10.       DATE OR REVISION OF THE TEXT

September 2009April 2014           

1.         TRADE NAME OF THE MEDICINAL PRODUCT

 

Glypressin  1 mg/ 8.5 ml solution for injection

2.         Qualitative And Quantitative Composition 

8.5 ml of injection solution contains 1 mg1mg Terlipressin Acetate (0.12 mg/ml) and 1.33 mmol of sodium.

                   

For a full list of excipients see section 6.1.

3.         Pharmaceutical Form

Solution for injection.

Clear, colourless aqueous fluid.

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 (iInternational 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 (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.

2)  In type 1 hepatorenal syndrome:

An i.v. injection 3 to 4 mg (3x8.5ml to 4x8.5ml) 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. 

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 medicamentsmedicinal products and other forms of interaction

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 reflexofenic inhibition of the cardiac activity via the vagus nerve due to 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 any transfer of Glypressin to breast milk is insufficient.  Glypressin should not be used in breast feeding women.

Lactation

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.

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.

MedDRA System Organ Class	COMMON	UNCOMMON	RARE	Not known
Disorder	(10-1%)	(1-0.1%)	(0.1-0.01%)	(cannot be estimated from the available data)
Metabolism and nutrition disorders		Hyponatraemia if fluid not monitored
Nervous system disorders	Headache
Cardiac disorders	Bradycardia	Atrial Fibrillation		Torsade de pointes
		Ventricular Extracystoles		Cardiac failure
		Tachycardia
		Chest pain
		Myocardial Infarction
		Fluid overload with pulmonary oedema Torsades de pointe Cardiac failure
Vascular disorders	Peripheral vasoconstriction	Intestinal ischaemia
	Peripheral ischemia	Peripheral cyanosis
	Facial pallor	Hot flushes
	Hypertension
Respiratory, thoracic and mediastinal disorders		Respiratory distress	Dyspnoea
		Respiratory failure
Gastrointestinal disorders	Transient abdominal cramps	Transient nausea
	Transient diarrhoea	Transient vomiting
Skin and subcutaneous tissue disorders				Skin necrosis
Pregnancy, puerperium and perinatal conditions				Uterine constriction Decreased uterine blood flowUterine ischemia
General disorders and administration site disorders		Injection site necrosis

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 mg2mg terlipressin acetate/4 hours) 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.

5.         Pharmacological Properties

5.1       Pharmacodynamic properties

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

ATC code: H01B A04

 

Terlipressin initially has an effect of its own, but is converted by enzymatic cleavage to lysine vasopressin. 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 as the higher dose produces a dependable effect throughout the period of treatment (4 hours)

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 (T1/2a)) is about 8-10 minutes.

The half-life of elimination (T1/2b)) 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         

Sodium chloride

Acetic acid

Sodium acetate

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

2 years            

6.4       Special precautions for storage

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

6.5      Nature and contents of container

Each carton contains five clear hydrolytic class 1 glass ampoules, 10ml nominal volume. 

The ampoule has a coloured dot indicating the cut area. It contains 8.5ml of solution for injection.  

6.6       Instructions for use / handling

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

Each ampoule is 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

            PA 1009/4/2

9.         Date Of First Authorisation / Renewal Of Authorisation

            25^th September 2009

10.       DATE OR REVISION OF THE TEXT

September 2009April 2014           

Update SPC following EU PSUR harmonisation scheme

Update SPC following EU PSUR harmonisation scheme

None provided

None provided