GIAPREZA 2.5mg / ml perfusive solution concentrate medication leaflet

Giapreza 2.5 mg/ml concentrate for solution for infusion

Each ml of concentrate contains angiotensin II acetate equivalent to 2.5 mg angiotensin II.

One vial of 1 ml concentrate for solution for infusion contains 2.5 mg of angiotensin II.

One vial of 2 ml concentrate for solution for infusion contains 5 mg of angiotensin II.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear and colourless solution.pH: 5.0 to 6.0

Osmolality: 130 to 170 mOsm/kg

Giapreza is indicated for the treatment of refractory hypotension in adults with septic or otherdistributive shock who remain hypotensive despite adequate volume restitution and application ofcatecholamines and other available vasopressor therapies (see section 5.1).

Giapreza should be prescribed by a physician experienced in the treatment of shock and is intended foruse in an acute and hospital setting.

The recommended starting dose of Giapreza is 20 nanograms (ng)/kg per minute via continuousintravenous infusion.

When initiating, it is important to closely monitor blood pressure response and adjust doseaccordingly. Concurrent venous thromboembolism (VTE) prophylaxis should be used unlesscontraindicated during treatment with Giapreza (see section 4.4).

Once an infusion has been established, the dose may be titrated as frequently as every 5 minutes insteps of up to 15 ng/kg per minute, as needed, depending on the patient’s condition and target meanarterial pressure. Approximately one in every four patients experienced transient hypertension with theangiotensin II 20 ng/kg per minute starting dose in clinical trials (see section 4.8), thus needing dosedown-titration. For critically ill patients, the usual target mean arterial pressure is 65 - 75 mmHg. Donot exceed 80 ng/kg per minute during the first 3 hours of treatment. Maintenance doses should notexceed 40 ng/kg per minute. Doses as low as 1.25 ng/kg per minute may be used.

It is important to administer Giapreza at the lowest compatible dose to achieve or maintain adequatearterial blood pressure and tissue perfusion (see section 4.4). The median duration of treatment inclinical trials was 48 hours (range: 3.5 to 168 hours).

In order to minimise the risk of adverse events derived from prolonged vasoconstriction, treatmentwith Giapreza should be withdrawn once underlying shock is sufficiently improved. Down-titrate bygradual decrements of up to 15 ng/kg per minute, as needed, based on blood pressure, in order to avoidhypotension due to abrupt withdrawal (see section 4.4).

There are limited efficacy and safety data of Giapreza in patients > 75 years. No special doseadjustment is required in patients over 75 years. As for other age groups, it is important to closelymonitor blood pressure response and adjust dose accordingly.

No special dose adjustment is required in patients with renal insufficiency or those with hepaticimpairment (see section 5.2). As for other patient populations, it is important to closely monitor bloodpressure response and adjust dose accordingly.

The safety and efficacy of Giapreza in children less than 18 years old has not yet been established. Nodata are available.

Giapreza should only be administered by continuous intravenous infusion under close monitoring ofhaemodynamics and end-organ perfusion.

For intravenous use only after dilution. Giapreza is recommended to be administered via a centralvenous line.

For instructions on dilution of the medicinal product before administration, see section 6.6.

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

The clinical experience with Giapreza is limited to septic or other distributive shock. The use of

Giapreza is not recommended in other types of shock (e.g. cardiogenic shock, etc) as patients withnon-distributive shocks were excluded from clinical trials (see section 5.1).

Thromboembolic events have been reported with the use of angiotensin II in clinical trials. The majorimbalance compared to placebo was in venous thromboembolism (6.1% vs 0%) (see section 4.8).

Concurrent venous thromboembolism (VTE) prophylaxis should be used unless contraindicated duringtreatment with Giapreza. Non-pharmacologic VTE prophylaxis may be considered wherepharmacologic prophylaxis is contraindicated.

Peripheral ischaemia

Peripheral ischaemia has been reported with the use of angiotensin II (see section 4.8). It is importantto administer Giapreza at the lowest compatible dose to achieve or maintain adequate mean arterialpressure and tissue perfusion.

Withdrawal of therapy

Giapreza should be gradually decreased since patients may experience hypotension or worsening ofthe underlying diagnosis of shock on abrupt withdrawal or premature discontinuation (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per 2.5 mg/ml, that is to sayessentially ‘sodium-free’.

No interaction studies have been performed. No in vitro metabolism studies have been performed with

Giapreza.

Patients who have recently received angiotensin converting enzyme (ACE) inhibitors may be moresensitive to Giapreza’s action with an increased response. Patients who have recently receivedangiotensin II receptor blockers (ARBs) may be less sensitive to Giapreza’s actions with a reducedresponse.

Concomitant administration of Giapreza and other vasopressors may have an additive effect on meanarterial pressure (MAP). The addition of Giapreza may require a reduction in doses of othervasopressors (e.g. adrenergic or dopaminergic agents).

There is a limited amount of data from the use of angiotensin II in pregnant women. Animal studiesare insufficient with respect to reproductive toxicity. Use during pregnancy should be avoided ifpossible and the potential benefit to the patient weighed against any possible risk to the foetus.

It is unknown whether angiotensin II or its metabolites are excreted in human milk. A risk to thesuckling child cannot be excluded. Breast-feeding should be discontinued during treatment with

Giapreza.

There are no data available on the potential effects on fertility in humans.

Not relevant.

The adverse reactions described in this section were identified in the pivotal clinical trial (N = 163treated with Giapreza). The most frequent adverse reactions reported in the Giapreza versus placeboarm are thromboembolic events (12.9% vs 5.1%) and transient hypertension (22.7% vs 1.9%)respectively.

Table 1 lists the adverse reactions recorded in clinical trials in the total safety population treated with

Giapreza by MedDRA system organ class and frequency. Frequency categories are defined as: verycommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to< 1/1 000), and very rare (< 1/10 000).

Table 1: Frequency of adverse reactions

MedDRA System organ class Very common Common

Cardiac disorders Tachycardia

Vascular disorders Thromboembolic eventsa Peripheral ischaemia

Transient hypertensionba Grouped term to include arterial and venous thrombotic eventsb Defined as an increase in mean arterial pressure > 100 mmHg

Transient hypertension

A total of 37 patients (23%) experienced transient hypertension with the angiotensin II 20 ng/kg/minstarting dose. Transient hypertension may be promptly mitigated by dose down-titration (seesection 4.2).

More patients experienced venous and arterial thromboembolic events in the Giapreza arm comparedto placebo arm in the Phase 3 (ATHOS-3) study (21 [12.9%] vs 8 [5.1%]). The major imbalancecorresponded to venous thromboembolism (10 [6.1%] vs 0 [0%] respectively). Of these, 7 casescorresponded to deep vein thrombosis. Two (1.2%) patients in the Giapreza arm experienced a fatalthromboembolic event compared with no patients in the placebo arm. Concurrent venousthromboembolism prophylaxis should be used unless contraindicated during treatment with Giapreza(see section 4.4).

Peripheral ischaemia

More patients experienced peripheral ischaemia in the Giapreza arm compared to the placebo arm(7 [4.3%] vs 4 [2.5%]). Of them, 5 cases (3.1%) in the Giapreza arm and 3 (1.9%) cases in the placeboarm were considered serious. One patient in each arm discontinued treatment as a result. Peripheralischaemia may be a consequence of the mechanism of action of Giapreza. It is important to administer

Giapreza at the lowest compatible dose to achieve or maintain adequate mean arterial pressure andtissue perfusion. In order to minimise adverse events derived from prolonged vasoconstriction,treatment should be withdrawn as soon as the underlying shock is sufficiently improved (seesections 4.2 and 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose may result in severe hypertension. Down-titration of therapy, careful observation, andinitiation of appropriate supportive measures are the indicated treatment of overdose of angiotensin II.

Hypertensive effects are expected to be brief because the half-life of angiotensin II is less than oneminute.

Pharmacotherapeutic group: Cardiac therapy, other cardiac stimulants, ATC code: C01CX09

Mechanism of action and pharmacodynamic effects

Angiotensin II raises blood pressure by vasoconstriction; increased aldosterone release via directaction of angiotensin II on the vessel wall is mediated by binding to the G-protein-coupledangiotensin II receptor type 1 on vascular smooth muscle cells which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction.

Giapreza is titrated to effect for each individual patient. In the ATHOS-3 trial, the median time toincrease blood pressure was approximately 5 minutes. The effect on blood pressure is sustained for atleast the first three hours of continuous intravenous infusion. Due to the short half-life ofangiotensin II (less than one minute), an abrupt withdrawal of angiotensin II may lead to reboundhypotension (see section 4.4). Therefore, once underlying shock is sufficiently improved, a slowdown-titration is recommended by gradual decrements of up to 15 ng/kg per minute, as needed, basedon blood pressure (see sections 4.2 and 4.4).

The angiotensin II for the Treatment of High-Output Shock (ATHOS-3) was a Phase 3 randomised,placebo-controlled, double-blind, international, multi-centre safety and efficacy trial in which321 adults with septic or other distributive shock who remained hypotensive despite fluid andvasopressor therapy were randomised 1:1 to Giapreza or placebo. Doses of Giapreza or placebo weretitrated to a target mean arterial pressure (MAP) of ≥ 75 mmHg during the first 3 hours of treatmentwhile doses of other vasopressors were maintained. From Hour 3 to Hour 48, Giapreza or placebowere titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors.

For their inclusion in the trial, patients had to have clinical features of high-output shock defined as acardiac index > 2.3 l/min/m2 or the sum of central venous oxygen saturation > 70% with centralvenous pressure (CVP) > 8 mmHg. Patients also had to have catecholamine refractory hypotension(CRH) defined as requiring a total sum vasopressor dose of > 0.2 mcg/kg/min for 6 to 48 hours, tomaintain a mean arterial pressure (MAP) between 55-70 mmHg and receiving at least 25 ml/kg ofcrystalloid or colloid equivalent over the previous 24-hour period and be adequately volumeresuscitated in the opinion of the treating investigator.

Of the 321 patients treated in the Phase 3 trial, 195 patients were male (60.7%), 257 (80%) patientswere White, 33 (10%) were Black, and 31 (10%) were Other. Median age was 64 years (range:22-89 years). Patients requiring high doses of steroids, patients with a history of asthma orbronchospasm who were not mechanically ventilated, and patients with Raynaud’s syndrome wereexcluded. Patients with active bleeding, mesenteric ischaemia, liver failure and MELD score of ≥ 30,

CV SOFA score ≤ 3 and patients with extensive burns were also excluded. 91% of subjects had septicshock; the remaining subjects had other forms of distributive shock such as neurogenic shock. Patientswith cardiogenic shock were excluded (see section 4.4).

At the time of study drug administration, 97% of subjects were receiving norepinephrine,67% vasopressin, 15% phenylephrine, 13% epinephrine, and 2% dopamine. 83% of subjects hadreceived two or more vasopressors and 47% three or more vasopressors prior to study drugadministration. Patients were not necessarily on maximum doses of other vasopressors at the time ofrandomisation. Of the 321 patients, 227 (71%) were receiving a baseline norepinephrine equivalentdose (NED) < 0.5 mcg/kg/min, 73 patients (23%) were receiving baseline NED ≥ 0.5 to< 1 mcg/kg/min and 21 (6%) patients were receiving high doses of vasopressors(NED ≥ 1.0 mcg/kg/min). The effect of Giapreza when added to maximum doses of other vasopressorsis unknown.

The primary endpoint was the percentage of subjects who achieved either a MAP ≥ 75 mmHg or a≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours.

The primary endpoint was achieved by 70% of patients randomised to Giapreza compared to 23% ofplacebo subjects; p < 0.0001 (a treatment effect of 47%). The treatment effect was consistent in high-risk subsets of patients with low baseline MAP or high APACHE II score, which were stratificationvariables (Table 2).

Table 2: Primary efficacy endpoints: MAP response at hour 3 (mITT population andsubgroups)

Subgroup Placebo Giaprezaresponse rate response rate

All patients 37/158 patients 114/163 patients23% 70%

Baseline MAP < 65 mmHg 10/50 patients 28/52 patients20% 54%

Baseline APACHE II > 30 17/65 patients 38/58 patients26% 66%mITT=modified intent-to-treat population

In the Giapreza-treated group, the median time to reach the target MAP endpoint was 5 minutes. Theeffect on MAP was sustained for at least the first three hours of treatment. The median dose of

Giapreza was 10 ng/kg/min at 30 minutes. Of the 114 responders at Hour 3, only 2 (1.8%) receivedmore than 80 ng/kg/min.

Mortality through day 28 was 46% on Giapreza and 54% on placebo (hazard ratio 0.78; 95%confidence interval 0.57-1.07).

The effect of Giapreza on morbidity and mortality has not been determined in appropriate studies.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Giapreza in one or more subsets of the paediatric population for the treatment of hypotension inchildren who remain hypotensive despite fluid and vasopressor therapy.

Giapreza is titrated to effect for each individual patient. Plasma levels of angiotensin II were evaluatedat baseline and hour 3 of infusion in the phase 3 pivotal trial.

No specific studies have been conducted to investigate the distribution of Giapreza.

No specific studies have been conducted to investigate the metabolism and excretion of Giapreza.

The plasma half-life of angiotensin II administered intravenously is less than one minute. It ismetabolised by end terminal cleavage (at both the amino and carboxy termini) in a variety of tissuesincluding erythrocytes, plasma and many of the major organs (i.e., intestine, kidney, liver and lung).

No trials have been conducted to investigate the pharmacokinetics of angiotensin II in renally impairedpatients since the kidneys are not a major organ for angiotensin II metabolism or excretion.

No trials have been conducted to investigate the pharmacokinetics of angiotensin II in patients withhepatic impairment since the liver is not a major organ for angiotensin II metabolism or excretion.

In a cardiovascular safety pharmacology study in normotensive dogs, Giapreza elicited increased heartrate, systemic vascular resistance, left ventricular systolic pressure and left ventricular diastolicpressure, and PR interval prolongation.

In a 48-hour continuous intravenous administration of angiotensin II in neonatal lambs, the nominaldose rates of 4, 12 and 40 ng/kg/min were well tolerated. No treatment related adverse effects wereobserved.

Mannitol

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial3 years

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature and2°C - 8 °C diluted in sodium chloride 9 mg/ml (0.9%) solution for injection. From a microbiologicalpoint of view, the product should be used immediately. If not used immediately, in-use storage timesand conditions prior to use are the responsibility of the user and would normally not be longer than24 hours at 2 °C - 8 °C or 25 °C.

Store in a refrigerator (2 °C - 8 °C).

For storage conditions after dilution of the medicinal product, see section 6.3.

1 ml vial1 ml solution in a Type I glass vial with an aluminium over-seal, stopper (elastomeric), and plasticcap. Pack size of 1 or 10 vials per carton.

2 ml vial2 ml solution in a Type I glass vial with an aluminium over-seal, stopper (elastomeric), and plasticcap. Pack size of 1 vial per carton.

Not all pack sizes may be marketed.

For single dose only.

Instructions for preparation of the medicinal product before administration1. Inspect each vial for particulate matter prior to dilution.2. Dilute 1 or 2 ml of Giapreza in sodium chloride 9 mg/ml (0.9%) solution for injection toachieve a final concentration of 5 000 ng/ml or 10 000 ng/ml.3. Diluted solution should be clear and colourless.4. Discard the vial and any unused portion of the medicinal product after use.

Table 3: Preparation of diluted solution

Fluid Vial Withdraw Infusion Finalrestricted? strength amount bag size concentration(ml) (ml) (ng/ml)

No 2.5 mg/ml 1 500 5 0002.5 mg/ml 1 250 10 000

Yes5 mg/2 ml 2 500 10 000

Diluted solution may be stored at room temperature or under refrigeration. Discard prepared solutionafter 24 hours at room temperature or under refrigeration.

Giapreza may be co-administered with norepinephrine, epinephrine, vasopressin, terlipressin,dopamine, and/or phenylephrine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

PAION Pharma GmbH

Heussstraße 2552078 Aachen

Germany

EU/1/19/1384/001

EU/1/19/1384/002

EU/1/19/1384/003

Date of first authorisation: 23 August 2019

Date of lastest renewal: 16 May 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu