Argipressin Vantage 20 IU/ml solution for injection – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Argipressin Vantage 20 IU/ml solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 20 IU (international units) of argipressin (in form of acetate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection

clear, colourless liquid, free from the visible particles.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For use in

• Treatment of diabetes insipidus (excluding nephrogenic diabetes insipidus);
• Control of bleeding esophageal varices;
• In adults with septic shock as (subset of vasodilatory shock) who remain hypotensive despite fluids and norepinephrine.

4.2 Posology and method of administration

Posology

Adults

Diabetes insipidus:

Argipressin Vantage is administered at a dose of 0.25 ml to 1 ml (5-20 IU) by subcutaneous or intramuscular injection every 4 hours.

Oesophageal Varices:

For the initial control of variceal bleeding Argipressin Vantage should be given intravenously. Argipressin Vantage, 20 units diluted in 100 ml glucose 5% w/v may be infused over a 15 minute period.

Septic shock:

Therapy with Argipressin Vantage should be started within the first 6 hours after the onset of septic shock. Argipressin Vantage is added to conventional vasopressor therapy with norepinephrine with the intent of raising mean arterial pressure (MAP) to target.

Start with a dose of 0.01 IU/min by continuous intravenous infusion. If the target blood pressure response is not achieved, titrate by 0.005 IU/min at 10- to 15-minute intervals up to 0.03 IU/min. Argipressin Vantage should be used for a limited period necessary to maintain the target blood pressure (usually, 24-96 h). Discontinuing norepinephrine first may confer a lower incidence of rebound hypotension. Do not discontinue Argipressin Vantage abruptly, taper by 0.005 IU/min every hour as tolerated to maintain target blood pressure.

Method of administration

Subcutaneous, intravenous or intramuscular injection.

Paediatric population

Argipressin Vantage is not recommended in children and adolescents under 18 years old.

Elderly

Clinical studies of vasopressin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy

Hepatic impairment

As no clinical studies have been carried out in patients with hepatic impairment, the treatment recommendations are not established for patients with hepatic impairment.

Renal impairment

As no clinical studies have been carried out in patients with renal impairment, the treatment recommendations are not established for patients with renal impairment.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Anaphylaxis to the active substance or to the excipients listed in section 6.1. Patient with coronary artery disease or those intended to receive halogenated anaesthetic agents.

Chronic nephritis (until residual nitrogen blood levels are improved). Vascular disease (especially coronary arteries disease).

4.4 Special warnings and precautions for use

In septic shock, Argipressin Vantage should only be started if target arterial blood pressure cannot be maintained with adequate fluid substitution and administration of catecholamines.

Patients with impaired cardiac response may experience worsening cardiac output. Aggressive treatment in patients with vasodilatory shock can compromise perfusion of organs, including those of the gastrointestinal tract.

During vasopressin therapy, electrocardiogram (ECG), fluid and electrolyte status should be monitored.

The skin condition should be monitored in patients with peripheral vascular disease for the signs of ischemia (pain, changes in color, temperature, or sensation, absence of pulse in the extremities).

The drug can cause fluid retention. The first symptoms of this condition are drowsiness, lethargy, headache, in severe cases coma and convulsions.

Caution should be used in patients with epilepsy, migraine, asthma, heart failure or any state in which a rapid increase of extracellular water may produce hazard for an already overburdened system.

4.5 Interaction with other medicinal products and other forms of interaction

Increasing of Argipressin Vantage activity:

Pressor effects of catecholamines and Argipressin Vantage are expected to be additive on mean arterial blood pressure and other hemodynamic parameters. No separate clinical studies examining the effect of the combined use of vasopressin with catecholamines other than epinephrine have been found in the available literature. One big epidemiological study exists indicating a practice of combining vasopressin with other catecholamines in septic shock, however its effectiveness has not been studied.

Indomethacin may prolong effects of Argipressin Vantage on cardiac index and systemic vascular resistance.

Ganglionic blockers coadministration may increase the effect of Argipressin Vantage on mean arterial blood pressure.

Furosemide coadministration increases the effect of Argipressin Vantage on osmolar clearance and increases urine flow. In healthy volunteers, coadministration of furosemide and vasopressin resulted in a 4-fold increase in osmolar clearance and 9-fold increase of urine flow.

The following drugs may potentiate the antidiuretic effect of Argipressin Vantage when used concurrently: carbamazepine, chlorpropamide, clofibrate, fludrocortisone, and urea.

Use with drugs suspected of causing SIADH e.g.: SSRI (fluoxetine, paroxetine, sertraline, fluvoxamine), tricyclic antidepressants, haloperidol or felbamate, may increase the pressor effect and antidiuretic effect of Argipressin Vantage.

Decreasing of Argipressin Vantage activity:

Use with drugs suspected of causing diabetes insipidus (e.g., demeclocycline, lithium, foscarnet,

clozapine) may decrease the pressor effect and antidiuretic effect of Argipressin Vantage.

Alcohol may block the antidiuretic activity of Argipressin Vantage.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate or well-controlled studies of Argipressin Vantage in pregnant women. It is not known whether vasopressin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal study revealed harmful effect of vasopressin infusion in miece offspring. Use during pregnancy should be avoided if possible and the potential benefit to the patient weighed against any possible risk to the foetus.

Lactation

It is not known whether vasopressin is present in human milk. However, oral absorption by a nursing infant is unlikely because vasopressin is rapidly destroyed in the gastrointestinal tract. Consider advising a lactating woman to pump and discard breast milk for 1.5 hours after receiving vasopressin to minimize potential exposure to the breastfed infant.

Fertility

No formal fertility studies have been performed with vasopressin. Several animal studies revealed negative effects on sperm motility.

4.7 Effects on ability to drive and use machines

Argipressin Vantage may cause dizziness. This should be taken into account when driving vehicles and using machines.

4.8 Undesirable effects

Tabulated list of adverse reactions

Adverse reactions are presented in table below. Adverse reactions are listed according to MedDRA primary system organ class. Frequencies are defined as follows: 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 (cannot be estimated from the available data).

The following adverse reactions associated with the use of vasopressin were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overdosage with Argipressin Vantage can be expected to manifest as consequences of vasoconstriction of various vascular beds (peripheral, mesenteric, and coronary) and as hyponatremia.

Overdosage may lead less commonly to ventricular tachyarrhythmias (including Torsade de Pointes), rhabdomyolysis, and non-specific gastrointestinal symptoms. Direct effects will resolve within minutes of withdrawal of treatment.

Fluid retention occurs in overdose. Fluids should be restricted. In very severe cases, hypertonic saline solutions may be administered.

Brain oedema may require osmotic diuretics.

Sublingual nitroglycerin is recommended in cardiac pain.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Systemic hormonal preparations. Posterior pituitary lobe hormones. Vasopressin and analogues.

ATC code: Н01В А01

Mechanism of action

The antidiuretic action of argipressin is ascribed to increase in reabsorption of water by the renal tubules. Argipressin Vantage can cause contraction of smooth muscle of the gastrointestinal tract, gall bladder, urinary bladder and all parts of the vascular bed, especially the capillaries, small arterioles and venules. It has less effect on the smooth musculature of the large veins. The direct effect on the contractile elements is neither antagonized by adrenergic blocking agents nor prevented by vascular denervation.

5.2 Pharmacokinetic properties

Absorption

Following subcutaneous or intramuscular administration of Argipressin Vantage injection, the duration of antidiuretic activity is variable, but effects are usually maintained for 2-8 hours.

Biotransformation

The majority of the dose of Argipressin Vantage is metabolized and rapidly destroyed in the liver and kidneys. Argipressin Vantage has a plasma half-life period of about 10-20 minutes.

Elimination

Approximately 5% of a subcutaneous dose of Argipressin Vantage is excreted unchanged in the urine 4 hours after dosing.

5.3 Preclinical safety data

Preclinical safety data does not add anything of further significance to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Acetic acid, water for injection

6.2 Incompatibilities

Unknown

6.3 Shelf life

Unopened: 2 years

After the first opening: for immediate further dilution.

After dilution of 20 IU (1 ml) of Argipressin Vantage in 100 ml of 5% glucose: for immediate use.

After dilution with 0.9 % sodium chloride or 5% glucose to either 0.1 units/mL or 1 unit/mL:

Chemical and physical in-use stability after dilution has been demonstrated for 18 hours at room temperature or 24 hours at 2 °C – 8 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in refrigerator (2 C – 8 C). Do not freeze.

Keep out of reach of children.

For storage conditions after first opening and dilution of the medicinal product, see section 6.3

6.5 Nature and contents of container

Clear hydrolytic class I glass 1 ml ampoule with breaking ring. 10 ampoules per carton.

6.6 Special precautions for disposal

Argipressin Vantage 20 IU/ml solution for injection must be diluted prior to intravenous administration.

For the treatment of variceal bleeding, dilute 20 IU (1 ml) of Argipressin Vantage in 100 ml of 5% glucose.

For the treatment of septic chock, dilute Argipressin Vantage with 0.9% sodium chloride or 5% glucose solution (the volume of diluent depends on patient’s fluid status):

• if patient is not fluid restricted - to 0.1 IU/ml (mix 50 IU [2.5 mL] of

  Argipressin Vantage with 500 mL of diluent);

• if patient is fluid restricted - to 1 IU/ml (mix 100 IU [5 mL] of Argipressin

  Vantage with 100 mL of diluent).

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Vantage Pharmaceuticals Ltd.

Ravalco House, Cleveland Way,

Hemel Hempstead, Hertfordshire

HP2 7DL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 54054/0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

16/06/2022

10 DATE OF REVISION OF THE TEXT

16/06/2022