Treatment of idiopathic or heritable pulmonary arterial hypertension (PAH) to improve exercise tolerance and symptoms of the disease in patients classified as New York Heart Association (NYHA) functional class III.

 

Trisuva is used in adults (18 years and older).

 

Trisuva is administered by subcutaneous or intravenous ontinuous infusion. Due to the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, subcutaneous infusion (undiluted) is the preferred mode of administration and continuous intravenous infusion should be reserved for patients stabilised with treprostinil subcutaneous infusion and who become intolerant of the subcutaneous route, and in whom these risks are considered acceptable.

 

The treatment should be initiated and monitored only by clinicians experienced in the treatment of pulmonary hypertension.

 

Dosage (posology)

 

In adults

 

Treatment initiation for patients new to prostacyclin therapy

 

Treatment should be initiated under close medical supervision in a medical setting able to provide intensive care.

 

The recommended initial infusion rate is 1.25 ng/kg/min. If this initial dose is poorly tolerated, the infusion rate should be reduced to 0.625 ng/kg/min.

 

Dose adjustments

The infusion rate should be increased under medical supervision in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week.

 

The dose should be adjusted on an individual basis and under medical supervision in order to achieve a maintenance dose at which symptoms improve and which is tolerated by patients with pulmonary arterial hypertension symptoms.

 

Efficacy in the main 12-week trials was only maintained if the dose was increased on an average 3-4 times per month. The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, whilst minimizing the excessive pharmacological effects of treprostinil.

 

Adverse effects, such as flushing, headache, hypotension, nausea, vomiting and diarrhoea, are generally dependent on the dose of treprostinil administered. They may decrease as treatment continues, but should they persist or become intolerable to the patient, the infusion rate may be reduced to diminish their intensity.

 

During follow-up phases of clinical trials the mean doses reached after 12 months were 26 ng/kg/min,

after 24 months they were 36 ng/kg/min, and after 48 months they were 42 ng/kg/min.

 

For patients with obesity (weighing > 30% more than ideal body weight) initial dose and following dose increments should be based on ideal body weight.

 

Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound in pulmonary arterial hypertension. It is therefore recommended that interruption of treprostinil therapy is avoided and that the infusion is re-started as soon as possible after an abrupt accidental dose reduction or interruption. The optimal strategy for reintroducing treprostinil infusion needs to be determined on a case by case basis by medically qualified personnel. In most cases, after an interruption of a few hours,

restarting of treprostinil infusion can be done using the same dose rate; interruptions for longer periods may require the dose of treprostinil to be re-titrated.

In elderly patients

 

Clinical studies of treprostinil did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In a population pharmacokinetic (PK) analysis, plasma clearance of treprostinil was reduced by 20%. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

 

Paediatric population

 

There are few data in patients less than 18 years of age. Available clinical studies do not establish whether the efficacy and safety of the recommended posology scheme for adults can be extrapolated to children and adolescents.

At-risk populations

 

Hepatic impairment

Plasma treprostinil exposure (area under the plasma concentration-time curve; AUC) increases by 260% to 510% in mild to moderate hepatic impairment, Child-Pugh classes A and B, respectively. Plasma clearance of treprostinil was reduced by up to 80% in subjects presenting with mild to moderate hepatic impairment. Caution is therefore advised when treating patients with hepatic impairment because of the risk of an increase in systemic exposure which may reduce tolerability and lead to an increase in dosedependent adverse effects.

 

 

The initial dose of treprostinil should be decreased to 0.625 ng/kg/min and incremental dose increases should be made cautiously.

 

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. As treprostinil and its metabolites are excreted mainly through the urinary route, caution is recommended when treating patients with renal impairment in order to prevent deleterious consequences related to the possible increase of systemic exposure.

 

Method of transition to intravenous epoprostenol treatment

 

When transition to intravenous epoprostenol is required, the transition phase should take place under strict medical supervision. It may be useful for guidance purposes to note the following suggested treatment transition scheme. Treprostinil infusions should first be decreased slowly by 2.5 ng/kg/min.

After at least 1 hour at the new treprostinil dose, epoprostenol treatment can be initiated at a maximum dose of 2 ng/kg/min. The treprostinil dose should then be decreased at subsequent intervals of at least 2 hours, and at the same time the epoprostenol dose is gradually increased after maintaining the initial dose for at least one hour.

 

Method of administration

 

For subcutaneous or intravenous administration

 

Administration by continuous subcutaneous infusion

 

Trisuva is administered by continuous subcutaneous infusion via a subcutaneous catheter using an ambulatory infusion pump.

 

In order to avoid potential interruptions in drug delivery, the patient must have access to a backup infusion pump and subcutaneous infusion sets in the event that the administration equipment should suffer an accidental malfunction.

 

The ambulatory infusion pump used to administer undiluted Trisuva subcutaneously should be:

 

1) small and lightweight,

2) capable of adjusting infusion rates in increments of approximately 0.002 ml/h,

3) fitted with occlusion, low battery, programming error and malfunction alarms,

4) accurate to within +/- 6% of the programmed delivery rate

5) positive pressure driven (continuous or pulsated).

 

The reservoir must be made of polyvinyl chloride, polypropylene or glass.

 

Patients must be thoroughly trained in the use and programming of the pump, and the connection and care of the infusion set.

 

Flushing the infusion line whilst connected to the patient may lead to accidental overdose.

 

Infusion rates ∇ (ml/h) are calculated using the following formula:

 

∇ (ml/h) = D (ng/kg/min) x W (kg) x [0.00006/treprostinil concentration (mg/ml)]

 

D = prescribed dose expressed in ng/kg/min

W = body weight of the patient expressed in kg

 

Trisuva is available at concentrations of 1mg/ml, 2.5 mg/ml, 5 mg/ml and 10 mg/ml.

 

For subcutaneous infusion, Trisuva is delivered without further dilution at a calculated Subcutaneous Infusion Rate (ml/h) based on a patient’s dose (ng/kg/min), Weight (kg), and the Vial Strength (mg/ml) of Trisuva being used (see table 1). During use, a single reservoir (syringe) of undiluted trepostinil can be administered for up to 14 days at 37°C.

 

The Subcutaneous Infusion rate is calculated using the following formula:

 

Subcutaneous                  Dose (ng/kg/min)  x  Weight (kg)  x  0.00006*

Infusion Rate       =   ------------------------------------------------------------------

(ml/h)                                          Trisuva Vial Strength (mg/ml)

 

 

*Conversion factor of 0.00006 = 60 min à hour x 0.000001 mg àng

 

Example calculations for Subcutaneous Infusion are as follows:

 

Example 1:

For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/ml Trisuva Vial Strength, the infusion rate would be calculated as follows:

 

Subcutaneous                        1.25 ng/kg/min x 60 kg x 0.00006

Infusion Rate        =    --------------------------------------------------------    =    0.005 ml/h

(ml/h)                                                        1 mg/ml

 

 

Example 2:

For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/ml Trisuva Vial Strength, the infusion rate would be calculated as follows:

 

 

 

Subcutaneous                         40 ng/kg/min  x  65 kg  x  0.00006

Infusion Rate            =    --------------------------------------------------------    =    0.031 ml/h

(ml/h)                                                             5 mg/ml

 

 

 

Table 1 provides guidance for Trisuva 10 mg/ml subcutaneous infusion delivery rates for patients of different body weights corresponding to doses of up to 155 ng/kg/min.

 

                                      Infusion rate setting of subcutaneous pump (ml/h) for Trisuva

                                                      at a treprostinil concentration of 10 mg/ml

 

                                                                        Patient Weight (kg)

Dose (ng/kg/min)	35	40	45	50	55	60	65	70	75	80	85	90	95	100
50	0.011	0.012	0.014	0.015	0.017	0.018	0.020	0.021	0.023	0.024	0.026	0.027	0.029	0.030
55	0.012	0.013	0.015	0.017	0.018	0.020	0.021	0.023	0.025	0.026	0.028	0.030	0.031	0.033
60	0.013	0.014	0.016	0.018	0.020	0.022	0.023	0.025	0.027	0.029	0.031	0.032	0.034	0.036
65	0.014	0.016	0.018	0.020	0.021	0.023	0.025	0.027	0.029	0.031	0.033	0.035	0.037	0.039
70	0.015	0.017	0.019	0.021	0.023	0.025	0.027	0.029	0.032	0.034	0.036	0.038	0.040	0.042
75	0.016	0.018	0.020	0.023	0.025	0.027	0.029	0.032	0.034	0.036	0.038	0.041	0.043	0.045
80	0.017	0.019	0.022	0.024	0.026	0.029	0.031	0.034	0.036	0.038	0.041	0.043	0.046	0.048
85	0.018	0.020	0.023	0.026	0.028	0.031	0.033	0.036	0.038	0.041	0.043	0.046	0.048	0.051
90	0.019	0.022	0.024	0.027	0.030	0.032	0.035	0.038	0.041	0.043	0.046	0.049	0.051	0.054
95	0.020	0.023	0.026	0.029	0.031	0.034	0.037	0.040	0.043	0.046	0.048	0.051	0.054	0.057
100	0.021	0.024	0.027	0.030	0.033	0.036	0.039	0.042	0.045	0.048	0.051	0.054	0.057	0.060
105	0.022	0.025	0.028	0.032	0.035	0.038	0.041	0.044	0.047	0.050	0.054	0.057	0.060	0.063
110	0.023	0.026	0.030	0.033	0.036	0.040	0.043	0.046	0.050	0.053	0.056	0.059	0.063	0.066
115	0.024	0.028	0.031	0.035	0.038	0.041	0.045	0.048	0.052	0.055	0.059	0.062	0.066	0.069
120	0.025	0.029	0.032	0.036	0.040	0.043	0.047	0.050	0.054	0.058	0.061	0.065	0.068	0.072
125	0.026	0.030	0.034	0.038	0.041	0.045	0.049	0.053	0.056	0.060	0.064	0.068	0.071	0.075
130	0.027	0.031	0.035	0.039	0.043	0.047	0.051	0.055	0.059	0.062	0.066	0.070	0.074	0.078
135	0.028	0.032	0.036	0.041	0.045	0.049	0.053	0.057	0.061	0.065	0.069	0.073	0.077	0.081
140	0.029	0.034	0.038	0.042	0.046	0.050	0.055	0.059	0.063	0.067	0.071	0.076	0.080	0.084
145	0.030	0.035	0.039	0.044	0.048	0.052	0.057	0.061	0.065	0.070	0.074	0.078	0.083	0.087
150	0.032	0.036	0.041	0.045	0.050	0.054	0.059	0.063	0.068	0.072	0.077	0.081	0.086	0.090
155	0.033	0.037	0.042	0.047	0.051	0.056	0.060	0.065	0.070	0.074	0.079	0.084	0.088	0.093

 

Administration by continuous intravenous infusion

 

Trisuva is administered by continuous intravenous infusion via a central venous catheter, using an ambulatory infusion pump. It may also be administered temporarily via a peripheral venous cannula, preferably placed in a large vein. Use of a peripheral infusion for more than a few hours may be associated with an increased risk of thrombophlebitis (see section 4.8).

 

When using an external infusion pump the patient must have access to a backup infusion pump and infusion sets in the event that the administration equipment malfunctions in order to avoid potential interruptions in drug delivery.

 

In general, the ambulatory infusion pump used to administer diluted Trisuva intravenously should:

 

1) be small and lightweight,

2) be capable of adjusting infusion rates in increments of approximately 0.05 ml/h.

3) have occlusion / no delivery, low battery, programming error and motor malfunction alarms,

4) have a maximal deviation of the adjusted flow rate of ±6% or better of the hourly dose

5) be positive pressure driven.

 

The reservoir should be made of polyvinyl chloride, polypropylene or glass.

 

 

Trisuva should be diluted with either sterile Water for injection or 0.9% (w/v) Sodium chloride for injection and is administered intravenously by continuous infusion, via a surgically placed indwelling central venous catheter or temporarily via a peripheral venous cannula, using an infusion pump designed for intravenous drug delivery.

 

When using an appropriate infusion pump and reservoir, a predetermined intravenous infusion rate should first be selected to allow for a desired infusion period. The maximum duration of use of diluted Trisuva should be no more than 24 hours (see section 6.3)

 

Typical intravenous infusion system reservoirs have volumes of 20, 50 or 100 ml. After determination of the required Intravenous Infusion Rate (ml/h) and the patient’s dose (ng/kg/min) and weight (kg), the Diluted Intravenous treprostinil Concentration (mg/ml) can be calculated using the following formula:

 

 

Step 1

 

 

Diluted                                Dose (ng/kg/min)    x     Weight (kg)    x     0.00006

Intravenous                 =   ------------------------------------------------------------------

Treprostinil                                 Intravenous Infusion Rate (ml/h)

Concentration                               

(mg/ml)

 

 

 

The amount of Trisuva needed to make the required Diluted Intravenous treprostinil concentration for the given reservoir size can then be calculated using the following formula:

 

 

 

 

 

 

Step 2

 

 

                                                     Diluted Intravenous

                                                           Treprostinil                       

                                                           Concentration                  

                                                                 (mg/ml)                         Total Volume of Diluted treprostinil

      Amount of Trisuva      =   ----------------------------------  x               Solution in Reservoir                

                  (ml)                            Trisuva Vial Strength                                      (ml)     

                                                                (mg/ml)

 

 

 

The calculated amount of Trisuva is then added to the reservoir along with a sufficient volume of diluent (sterile Water for injection or 0.9% Sodium chloride for injection) to achieve the desired total volume in the reservoir.

 

Example calculations for Intravenous Infusion are as follows:

 

Example 3:

For a 60 kg person at a dose of 5 ng/kg/min, with a predetermined intravenous infusion rate of 1 ml/h and a reservoir of 50 ml, the Diluted Intravenous treprostinil solution Concentration would be calculated as follows:

 

Step 1

 

Diluted

Intravenous                       5 ng/kg/min   x   60 kg   x   0.00006

Treprostinil              =    ---------------------------------------------------    =    0.018 mg/ml

Concentration                                                1 ml/h                             (18,000 ng/ml)     

(mg/ml)

 

 

 

The amount of Trisuva (using 1 mg/ml Vial Strength) needed for a total Diluted treprostinil Concentration of 0.018 mg/ml and a total volume of 50 ml would be calculated as follows:

 

 

Step 2

 

Amount of Trisuva     =       0.018 mg/ml    x   50 ml      =   0.9 ml

              (ml)                       ----------------------------------

                                                            1 mg/ml

             

 

The Diluted Intravenous treprostinil Concentration for the person in Example 3 would thus be prepared by adding 0.9 ml of 1 mg/ml Trisuva to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 50 ml in the reservoir. The pump flow rate for this example would be set at 1 ml/h.

 

Example 4:

For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion rate of 2 ml/h, and a reservoir of 100 ml, the Diluted Intravenous treprostinil Solution Concentration would be calculated as follows:

 

 

Step 1

 

Diluted

Intravenous                   30 ng/kg/min  x   75 kg   x   0.00006

Treprostinil        =      -------------------------------------------------    =   0.0675 mg/ml

Concentration                                        2mg/h                              (67,500 ng/ml)

(mg/ml)

 

 

The amount of Trisuva (using 2.5 mg/ml vial strength) needed for a total diluted treprostinil concentration of 0.0675 mg/ml and a total volume of 100 ml would be calculated as follows:

 

Step 2

 

                                            0.0675 mg/ml

Amount of Trisuva     =   --------------------     x  100 ml  =   2.7 ml

              (ml)                            2.5 mg/ml

 

 

 

The Diluted Intravenous treprostinil Concentration for the person in Example 4 would thus be prepared by adding 2.7 ml of 2.5 mg/ml Trisuva to a suitable reservoir along with a sufficient volume of diluent to achieve a total volume of 100 ml in the reservoir. The pump flow rate for this example would be set at 2 ml/h.

 

Table 2 provides guidance for the volume (ml) of Trisuva 10 mg/ml to be diluted in 20 ml, 50 ml or 100 ml reservoirs (0.4, 1 or 2 ml/h infusion rates, respectively) for patients of differing body weights corresponding to doses of up to 100 ng/kg/min.

 

Table 2

Volume (ml) of Trisuva 10 mg/ml to be diluted in cassettes or syringes 20 ml (0.4 ml/h infusion rate), 50 ml (1 ml/h infusion rate), 100 ml cassette (2 ml/h infusion rate)
Dose (ng/ kg/ min)	Patient Weight (kg)
	25	30	35	40	45	50	55	60	65	70	75	80	85	90	95	100
50	0.375	0.450	0.525	0.600	0.675	0.750	0.825	0.900	0.975	1.050	1.125	1.200	1.275	1.350	1.425	1.500
55	0.413	0.495	0.578	0.660	0.743	0.825	0.908	0.990	1.073	1.155	1.238	1.320	1.403	1.485	1.568	1.650
60	0.450	0.540	0.630	0.720	0.810	0.900	0.990	1.080	1.170	1.260	1.350	1.440	1.530	1.620	1.710	1.800
65	0.488	0.585	0.683	0.780	0.878	0.975	1.073	1.170	1.268	1.365	1.463	1.560	1.658	1.755	1.853	1.950
70	0.525	0.630	0.735	0.840	0.945	1.050	1.155	1.260	1.365	1.470	1.575	1.680	1.785	1.890	1.995	2.100
75	0.563	0.675	0.788	0.900	1.013	1.125	1.238	1.350	1.463	1.575	1.688	1.800	1.913	2.025	2.138	2.250
80	0.600	0.720	0.840	0.960	1.080	1.200	1.320	1.440	1.560	1.680	1.800	1.920	2.040	2.160	2.280	2.400
85	0.638	0.765	0.893	1.020	1.148	1.275	1.403	1.530	1.658	1.785	1.913	2.040	2.168	2.295	2.423	2.550
90	0.675	0.810	0.945	1.080	1.215	1.350	1.485	1.620	1.755	1.890	2.025	2.160	2.295	2.430	2.565	2.700
95	0.713	0.855	0.998	1.140	1.283	1.425	1.568	1.710	1.853	1.995	2.138	2.280	2.423	2.565	2.708	2.850
100	0.750	0.900	1.050	1.200	1.350	1.500	1.650	1.800	1.950	2.100	2.250	2.400	2.550	2.700	2.850	3.000

 

Training for patients receiving a continuous intravenous infusion

 

The clinical team responsible for the therapy must ensure that the patient is fully trained and competent to use the chosen infusion device. A period of personal instruction and supervision should continue until the patient is judged competent to change infusions, alter flow rates/doses as instructed, and be able to deal with common device alarms. Patients must be trained in proper aseptic technique when preparing the Trisuva infusion reservoir and priming the infusion delivery tubing and connection. Written guidance, either from the pump manufacturer or a specifically tailored advice by the prescribing physician, must be made available to the patient. This would include the required normal drug delivery actions, advice on how to manage occlusions and other pump alarms, and details of whom to contact in an emergency.

 

 

Minimising the risk of catheter-related blood stream infections – CR-BSI

 

Particular attention must be given to the following to help minimise the risk of catheter related blood stream infections in patients that are receiving treprostinil via intravenous infusion (see section 4.4).

This advice is in accordance with the current best practice guidelines for the prevention of catheterrelated blood stream infections, and includes:

 

 

General principles

 

- Use of a cuffed and tunnelled central venous catheter (CVC) with a minimum number of ports.

- insertion of the CVC using sterile barrier techniques.

- use of proper hand hygiene and aseptic techniques when the catheter is inserted, replaced, accessed, or repaired or when the catheter insertion site is examined and/or dressed.

- a sterile gauze (replaced every other day) or a sterile, semi-permeable dressing (replaced at least every seven days) should be used to cover the catheter insertion site.

- the dressing should be replaced whenever it becomes damp, loosened, or soiled or after examination of the site

- Topical antibiotic ointments or creams should not be applied, as they may promote fungal infections and antimicrobial-resistant bacteria.

 

Duration of use of diluted Trisuva solution

 

- the maximum duration of use of the diluted product should be no more than 24 hours.

 

Use of in-line 0.2 micron filter

 

- a 0.2 micron filter must be placed between the infusion tubing and the catheter hub and replaced every 24 hours at the time of changing the infusion reservoir

 

Two further recommendations that are potentially important for the prevention of water-borne Gram negative blood stream infections, relate to management of the catheter hub. These include:

 

Use of a split-septum closed hub system

 

- the use of a closed-hub system (preferably with a split septum rather than a mechanical valve device), ensures that the lumen of the catheter is sealed each time the infusion system is disconnected. This prevents the risk of exposure to microbial contamination;

- the split-septum closed-hub device should be replaced every 7 days.

 

Infusion system luer-lock inter-connections

 

The risk of contamination with water-borne Gram-negative organisms is likely to be increased if a luerlock inter-connection is wet at the time of exchanging either the infusion line or the closed hub Therefore:

 

- swimming and submersion of the infusion system at the site of connection with the catheter hub should be discouraged

- at the time of replacing the closed-hub device there should not be any water visible in the Luer- Lock connection threads

- the infusion line should only be disconnected from the closed hub device once every 24 hours at the time of replacement.

 

For special handling instructions see Section 6.6.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Pulmonary arterial hypertension related to veno-occlusive disease. - Congestive heart failure due to severe left ventricular dysfunction. - Severe liver impairment (Child-Pugh Class C). - Active gastrointestinal ulcer, intracranial haemorrhage, injury or other bleeding condition. - Congenital or acquired valvular defects with clinically relevant myocardial dysfunction not related to pulmonary hypertension. - Severe coronary heart disease or unstable angina; myocardial infarction within the last six months; decompensated cardiac failure if not under close medical supervision; severe arrhythmias; cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last three months.

The decision to initiate therapy with treprostinil should take into consideration the high probability that a continuous infusion will have to be continued for a prolonged period. Thus the patient's ability to accept and to be responsible for an indwelling catheter and infusion device should be carefully considered.

 

Treprostinil is a potent pulmonary and systemic vasodilator. In subjects presenting with low systemic arterial pressure, treprostinil treatment may increase the risk of systemic hypotension. Treatment is not recommended for patients with systolic arterial pressure of less than 85 mmHg.

 

It is recommended to monitor systemic blood pressure and heart rate during any change in dose with instructions to stop the infusion if symptoms of hypotension develop, or a systolic blood pressure of 85 mmHg or lower is detected.

 

Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound in pulmonary arterial hypertension (see section 4.2).

 

If a patient contracts pulmonary oedema while on treprostinil, the possibility of an associated pulmonary veno-occlusive disease should be considered. The treatment should be stopped.

 

Obese patients (BMI greater than 30 kg/m2) clear treprostinil more slowly.

 

The benefit of treprostinil subcutaneous treatment in patients with pulmonary arterial hypertension (NYHA functional class IV) has not been established.

 

The efficacy/safety ratio of treprostinil has not been studied in pulmonary arterial hypertension associated with left-right cardiac shunt, portal hypertension, or HIV infection.

 

Patients with hepatic and renal impairment should be dosed cautiously (see section 4.2).

 

As treprostinil and its metabolites are excreted mainly through the urinary route, caution is recommended when treating patients with renal impairment in order to prevent deleterious consequences related to the possible increase of systemic exposure (see section 4.2).

 

Caution is advised in situations where treprostinil may increase the risk of bleeding by inhibiting platelet aggregation.

 

Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g. gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration. Treprostinil dose reduction should be considered (see section 4.5).

 

Co-administration of a CYP2C8 enzyme inducer (e.g. rifampicin) may decrease exposure to treprostinil.

Decreased exposure is likely to reduce clinical effectiveness. Treprostinil dose increase should be considered (see section 4.5).

 

This medicinal product contains a maximum of 37.4 mg sodium per 10 mg/ml vial, equivalent to 1.9% of the WHO recommended maximum daily intake of 2g sodium for an adult.

 

 

Adverse events attributable to the intravenous drug delivery system

 

Central venous catheter associated blood stream infections and sepsis have been reported in patients receiving treprostinil by intravenous infusion. These risks are attributable to the drug delivery system.

A US Center for Disease Control retrospective survey of seven centres in the United States that used intravenous treprostinil for the treatment of PAH found an incidence rate for catheter-related bloodstream infections of 1.10 events per 1000 catheter days. Clinicians should be aware of the range of possible Gram-negative and Gram-positive organisms that may infect patients with long-term central venous catheters. Therefore, continuous subcutaneous infusion of undiluted Trisuva is the preferred mode of administration.

 

The clinical team responsible for the therapy must ensure that the patient is fully trained and competent to use the chosen infusion device (see section 4.2).

Associations to consider

 

+ Diuretics, antihypertensive agents, or other vasodilators Concomitant administration of treprostinil with diuretics, antihypertensive agents or other vasodilators increases the risk of systemic hypotension.

 

+ Platelet aggregation inhibitors, including NSAIDs and anticoagulants

Treprostinil may inhibit platelet function. Concomitant administration of treprostinil with platelet aggregation inhibitors, including NSAIDs, nitric oxide donors or anticoagulants may increase the risk of bleeding. Surveillance of patients taking anticoagulants should be closely maintained in accordance with conventional medical practice recommendations when monitoring such treatments. The concomitant use of other platelet inhibitors should be avoided in patients taking anticoagulants.

Continuous subcutaneous infusion of treprostinil had no effect on pharmacodynamics and pharmacokinetics of a single dose (25 mg) of warfarin. There are no data available on the potential interactions leading to increased risk of bleeding if treprostinil is co-prescribed with nitric oxide donors.

 

+ Furosemide

Treprostinil plasma clearance may be slightly reduced in patients treated with furosemide. This interaction is probably due to some common metabolic features shared by both compounds (carboxylate group glucuroconjugation).

 

+ Cytochrome P450 (CYP) 2C8 enzyme inducers/inhibitors

Gemfibrozil – Human pharmacokinetic studies with oral treprostinil diolamine indicated that coadministration of cytochrome P450 (CYP) 2C8 enzyme inhibitor gemfibrozil doubles the exposure (both Cmax and AUC) to treprostinil. It has not been determined if the safety and efficacy of treprostinil by the parenteral (subcutaneous or intravenous) route are altered by inhibitors of CYP2C8. If a CYP2C8 inhibitor (e.g. gemfibrozil, trimethoprim and deferasirox) is added to or subtracted from the patient’s medications after the titration period, treprostinil dose adjustment should be considered.

 

Rifampicin - Human pharmacokinetic studies with oral treprostinil diolamine indicated that coadministration of the CYP2C8 enzyme inducer rifampicin decreases exposure to treprostinil (by approximately 20%). It has not been determined if the safety and efficacy of treprostinil by the parenteral (subcutaneous or intravenous) route are altered by rifampicin. If rifampicin is added to or subtracted from the patient’s medications after the titration period, treprostinil dose adjustment should be considered.

 

CYP2C8 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's Wort) may reduce the exposure to treprostinil. If a CYP2C8 inducer is added to or subtracted from the patient’s medications after the titration period, treprostinil dose adjustment should be considered.

 

+ Bosentan

In a human pharmacokinetic study conducted with bosentan (250 mg/day) and treprostinil diolamine (oral dose 2 mg/day), no pharmacokinetic interactions between treprostinil and bosentan were observed.

 

+ Sildenafil

In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and treprostinil diolamine (oral dose 2 mg/day), no pharmacokinetic interactions between treprostinil and sildenafil were observed.

Pregnancy

 

No adequate data on the use of treprostinil in pregnant women are available. Animal studies are insufficient with respect to effects on pregnancy (see section 5.3). The potential risk for humans is unknown. Treprostinil should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the foetus.

 

Women of child-bearing potential Contraception is recommended during treprostinil treatment.

 

Breastfeeding

 

It is not known whether treprostinil is excreted in human milk. Breastfeeding women using treprostinil should be advised to discontinue breastfeeding.

Trisuva has a mild influence on the ability to drive and to use machines.

 

The initiation of treatment or dosage adjustments may be accompanied by undesirable effects such as symptomatic systemic hypotension or dizziness, which may impair the ability to drive and operate machinery.

Adverse reactions observed in placebo-controlled studies and post-marketing experience with

treprostinil are ranked according to frequency using the following convention:

 

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).

 

Tabulated list of adverse reactions

 

 

System organ class	Adverse reaction	Frequency
Nervous system disorders	Headache	Very common
	Dizziness	Common
Cardiac disorders	High output cardiac failure	Not known
Vascular disorders	Vasodilatation, flushing	Very common
	Hypotension	Common
	Bleeding event§	Common
	Thrombophlebitis*	Not known
Gastrointestinal disorders	Diarrhoea, nausea	Very common
	Vomiting	Common
Skin and subcutaneous tissue disorders	Rash	Very common
	Pruritus	Common
	Generalised rashes (macular or papular in nature)	Not known
Musculoskeletal, connective tissue and bone disorders	Jaw pain	Very common
	Myalgia, arthralgia	Common
	Pain in extremity	Common
	Bone pain	Not known

 

 

General disorders and administration site conditions	Infusion site pain, infusion site reaction, bleeding or haematoma.	Very common
	Oedema	Common
Blood and lymphatic system disorders	Thrombocytopenia	Not known
Infections and infestations	Central venous catheter-associated blood stream infection, sepsis, bacteraemia**	Not known
	Infusion site infection, subcutaneous infusion site abscess formation	Not known
	Cellulitis	Not known

 

* Cases of thrombophlebitis associated with peripheral intravenous infusion have been reported

** Life-threatening and fatal cases have been reported

§ See section «Description of selected adverse events»

 

Description of selected adverse events

 

Bleeding events

 

Bleeding events were common as expected in this patient population with a high proportion of patients treated with anticoagulants. Due to its effects on platelet aggregation, treprostinil may increase the risk of bleeding, as observed by an increased incidence of epistaxis and gastrointestinal (GI) bleeding (including gastrointestinal haemorrhage, rectal haemorrhage, gum haemorrhage and melaena) in controlled clinical trials. There were also reports of haemoptysis, haematemesis and haematuria, but these occurred with the same or lower frequency than in the placebo group.

 

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 national reporting system:

 

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5

1200 VIENNA

AUSTRIA

Fax: + 43 (0) 50 555 36207

Website: http://www.basg.gv.at/

 

Saudi-Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-Mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

Symptoms of overdose with Trisuva are similar to the effects of dose increases; they include flushing, headache, hypotension, nausea, vomiting, and diarrhoea. Patients experiencing symptoms of overdose should immediately reduce or discontinue their dose of treprostinil depending on the severity of the symptoms until the symptoms of overdose have resolved. Dosing should be recommenced with caution under medical control and patients monitored closely for recurrence of unwanted symptoms.

 

No antidote is known.

 

Pharmacotherapeutic group: PLATELET AGGREGATION INHIBITORS, EXCLUDING HEPARIN,

ATC code: B01AC21

 

Mechanism of action

Treprostinil is a prostacyclin analogue.

It exerts a direct vasodilation effect on the pulmonary and systemic arterial circulation and, inhibits platelet aggregation.

 

In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of treprostinil on the heart rate in animals varies with the dose. No major effects on cardiac conduction have been observed.

 

Clinical efficacy and safety

 

Data on efficacy in adults with pulmonary arterial hypertension:

 

Studies with subcutaneously administered treprostinil

 

Two phase III randomised, double-blind, placebo-controlled clinical trials have been conducted with treprostinil administered by subcutaneous continuous infusion in subjects with stable pulmonary arterial hypertension.

A total of 469 adults were included in the two trials: 270 presented with idiopathic or heritable pulmonary arterial hypertension (treprostinil group = 134 patients; placebo group = 136 patients), 90 patients presented with pulmonary arterial hypertension associated with connective tissue disease (mainly scleroderma) (treprostinil group = 41 patients; placebo group = 49 patients) and 109 patients presented with pulmonary arterial hypertension associated with congenital cardiopathy with left-right shunt (treprostinil = 58 patients; placebo = 51 patients).

At baseline, the mean 6-minute walking test distance was 326 metres + 5 in the group receiving treprostinil through subcutaneous infusion and 327 metres + 6 in the group receiving placebo. The dose of both treatments being compared was progressively increased during the study according to pulmonary arterial hypertension symptoms and clinical tolerance. The mean dose achieved after 12 weeks was 9.3 ng/kg/min in the treprostinil group and 19.1 ng/kg/min in the placebo group. After 12 weeks of treatment, the mean variation in the 6-minute walk test compared to baseline, calculated on the global population from both trials, was -2 metres ± 6.61 metres in the patients receiving treprostinil and -21.8 metres ± 6.18 metres in the placebo group. These results reflected a mean treatment effect assessed by the 6-minute walk test of 19.7 metres (p = 0.0064) compared to placebo for the global population from both trials.

 

Mean changes compared to baseline values in haemodynamic parameters (mean pulmonary arterial pressure (PAPm)), right atrial pressure (RAP), pulmonary vascular resistance (PVR), cardiac index (CI) and venous oxygen saturation (SvO2) showed treprostinil to be superior to placebo. The improvement in signs and symptoms of pulmonary hypertension (syncope, dizziness, chest pain, fatigue and dyspnoea) was statistically significant (p< 0.0001). In addition, the Dyspnoea-Fatigue Rating and Borg Dyspnoea Score were improved in patients treated with treprostinil after 12 weeks (p< 0.0001).

Analysis of a combined criterion associating the improvement of exercise capacity (6-minute walk test) of at least 10% compared to baseline after 12 weeks, an improvement by at least one NYHA class compared to baseline after 12 weeks and absence of deterioration in pulmonary hypertension together with a lack of death reported before week 12 for the global population of both studies showed the number of subjects responding to treprostinil to be 15.9% (37/233) while only 3.4% (8/236) of subjects in the placebo group responded. Sub-group analysis of the global population showed a statistically significant treatment effect of treprostinil compared to placebo on the 6-minute walk test in the sub-population of

subjects with idiopathic or heritable pulmonary arterial hypertension (p=0.043) but not in the sub-population of subjects with pulmonary arterial hypertension associated with scleroderma or congenital cardiopathy.

 

The effect seen on the primary endpoint (i.e., change in six minute walk distance after 12 weeks of treatment) was smaller than that seen in historical controls with bosentan, iloprost and epoprostenol.

No study directly comparing treprostinil and epoprostenol intravenous infusion has been conducted.

 

No specific study has been conducted in children with PAH.

 

There are no data from clinical studies conducted with an active comparator in patients with PAH.

Resorption and distribution

In humans, steady-state plasma concentrations are usually achieved within 15 to 18 hours of the initiation of either subcutaneous or intravenous infusion of treprostinil. Steady-state plasma concentrations of treprostinil are dose-proportional at infusion rates of 2.5 up to 125 ng/kg/min.

Subcutaneous and intravenous administration of treprostinil demonstrated bioequivalence at steady state at a dose of 10 ng/kg/min.

 

In a seven-day uninterrupted chronic pharmacokinetic study in 14 healthy volunteers with treprostinil doses ranging from 2.5 to 15 ng/kg/min administered by subcutaneous infusion, steady state plasma treprostinil concentrations reached peak levels twice (at 1 a.m. and 10 a.m. respectively) and trough levels twice (at 7 a.m. and 4 p.m. respectively). The peak concentrations were approximately 20% to 30% higher than the trough concentrations.

 

Biotransformation and elimination

The mean apparent elimination half-life following subcutaneous administration ranged from 1.32 to 1.42 hours after infusions over 6 hours, 4.61 hours after infusions over 72 hours, and 2.93 hours after infusions lasting at least three weeks. The mean volume of distribution for treprostinil ranged from 1.11 to 1.22 l/kg, and plasma clearance ranged from 586.2 to 646.9 ml/kg/h. Clearance is lower in obese subjects (BMI > 30 kg/m2).

 

In a study conducted on healthy volunteers using [14C] radioactive treprostinil, 78.6% and 13.4% of the subcutaneous radioactive dose were recovered in the urine and faeces respectively over a period of 224 hours. No single major metabolite was observed. Five metabolites were detected in the urine, ranging from 10.2% to 15.5% of the dose administered. These five metabolites accounted for a combined total of 64.4%. Three are products of oxidation of the 3-hydroxyloctyl side chain, one is a glucuro-conjugated derivative (treprostinil glucuronide) and one is unidentified. Only 3.7% of the dose was recovered in the urine as unchanged parent drug.

 

An in vitro study demonstrated no inhibitory potential of treprostinil to human hepatic microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A).

 

Moreover, administration of treprostinil had no inducing effect on hepatic microsomal protein, total cytochrome (CYP) P 450 content or on the activities of the isoenzymes CYP1A, CYP2B and CYP3A.

 

Clinical drug interaction studies have been carried out with paracetamol (4 g/day) and warfarin (25 mg/day) in healthy volunteers. These studies did not show a clinically significant effect on the

pharmacokinetics of treprostinil. A study conducted with warfarin found no apparent pharmacodynamic nor pharmacokinetic interaction between treprostinil and warfarin.

 

The metabolism of treprostinil mainly involves CYP2C8.

 

 

 

Special populations

 

Hepatic impairment:

In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic insufficiency, treprostinil at a subcutaneous dose of 10 ng/kg/min for 150 minutes had an AUC0-24 h that was increased 260% and 510%, respectively, compared to healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy adults (see section 4.2).

In 13 and 26 week studies continuous subcutaneous infusions of treprostinil sodium caused infusion site reactions in rats and dogs (oedema/erythema, masses/swellings, pain/sensitivity to touch). In dogs severe clinical effects (hypoactivity, emesis, loose stool and infusion site oedema) and death (associated with intestinal intussusceptions and rectal prolapse) were observed in animals administered ≥ 300 ng/kg/min.

Mean steady state plasma treprostinil levels of 7.85 ng/ml were measured in these animals. Plasma levels of this order may be achieved in humans treated with treprostinil infusions at > 50 ng/kg/min.

 

As a continuously sufficient exposure to treprostinil has not been proven for any dosage tested in the reproductive studies in rats, these studies might be insufficient regarding possible effects on fertility, prenatal and postnatal development.

 

No long-term animal studies have been performed to evaluate treprostinil’s carcinogenic potential. In vitro and in vivo genotoxicity studies did not show treprostinil to have any mutagenic or clastogenic effect.

 

In summary, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.

Metacresol

Sodium citrate (dihydrate)

Sodium chloride

Hydrochloric acid

Sodium hydroxide

Water for injection

No compatibility studies having been carried out, this medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.

Shelf life of the medicinal product as packaged for sale: 3 years Shelf-life of vial after first opening: 30 days at 30 °C maximum Shelf life during continuous subcutaneous infusion The chemical, physical and microbiological in-use stability of a single reservoir (syringe) of undiluted treprostinil administered via subcutaneous infusion could be established at 37°C for up to 14 days. Other storage times and conditions after first opening fall to the responsibility of the user. Shelf life during continuous intravenous infusion The chemical, physical and microbiological in-use stability of a single container (syringe) of diluted treprostinil solution administered via intravenous infusion could be established at 37°C for up to 24 hours. Other storage times and conditions after first opening fall to the responsibility of the user.

This medicinal product does not require any special storage conditions.

 

See section 6.3 for in-use storage times and conditions.

10 ml solution for infusion in a 10 ml borosilicate type I clear glass vial sealed with stoppers made of chlorobutyl-blended rubber with fluoropolymer coating secured with an aluminium flip-off crimp with a magenta-coloured polypropylene cap.

 

Each carton contains one vial.

Trisuva should be used undiluted, if it is administered via continuous subcutaneous infusion (see section 4.2).

 

Trisuva should be diluted with either sterile Water for injection or 0.9% (w/v) Sodium chloride for injection, if it is administered via continuous intravenous infusion (see section 4.2).

 

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