4.1. Therapeutic indications

Trepulmix is indicated for the treatment of adult patients with WHO Functional Class (FC) III or IV and:

- inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or

- persistent or recurrent CTEPH after surgical treatment to improve exercise capacity.

4.2. Posology and method of administration

Treatment with Trepulmix should be initiated and monitored only by clinicians experienced in the treatment of pulmonary hypertension. Treatment should be initiated under close medical supervision in a medical setting able to provide intensive care.

Posology

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 up to 1.25 ng/kg/min per week for the first four weeks of treatment and then up to 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 the patient.

During the follow-up phase of a clinical trial in CTEPH patients, the mean doses reached after 12 months were 31 ng/kg/min, after 24 months 33 ng/kg/min, and after 48 months 39 ng/kg/min. The respective maximum doses observed in the clinical trial were 52 ng/kg/min, 54 ng/kg/min and 50 ng/kg/min respectively.

Abrupt withdrawal or sudden marked reductions in the dose of treprostinil may cause a rebound of symptoms of chronic thromboembolic pulmonary 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 up to 4 hours, restarting of treprostinil infusion can be done using the same dose rate; interruptions for up to 24 hours may require a dose reduction of up to 50% of the most recent dose with a subsequent uptitration to the clinically effective dose. Longer periods of interruption may require the dose of treprostinil to be re-titrated from even lower flow rates. In any case, the reintroduction of treprostinil should be under medical supervision.

Special populations

Hepatic impairment

The initial dose of Trepulmix should be decreased to 0.625 ng/kg/min and incremental dose increases should be made cautiously (see section 5.2). Increments could be reduced to 0.625 ng/kg/min per dose increase, the final decision on the dose increments is at the discretion of the supervising physician.

Please note that “Severe hepatic impairment (Child-Pugh Class C) is listed as contraindication for use of treprostinil, see section 4.3.

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.

Elderly

No pharmacokinetic data of treprostinil in elderly is available. Caution is recommended when treating elderly patients due to higher incidence of hepatic and / or renal impairment.

Obese patients

Therapy of obese patients (weight ≥ 30% above ideal weight) should be initiated and increased with doses calculated based on their ideal weight. See section 5.2 for more information.

Paediatric population

There is no relevant use of treprostinil in children and adolescents for the indication of CTEPH.

Method of administration

Trepulmix is for subcutaneous use. It is administered undiluted by continuous infusion via a subcutaneous catheter using an ambulatory infusion pump.

The healthcare professional responsible for the therapy must ensure that the patient is fully trained and competent to use the chosen infusion device. All patients must be trained in preparation of the treprostinil infusion reservoir and priming of the infusion delivery tubing and connection. Written guidance, either from the pump manufacturer or specially tailored advice by the prescribing physician must be made available to the patient. This includes the required normal drug delivery actions, advice how to manage occlusions and other pump alarms, and details whom to contact in an emergency.

In order to avoid 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 Trepulmix subcutaneously, should be:

• small and lightweight,

• capable of adjusting infusion rates in increments of 0.002 ml/h or less,

• fitted with occlusion, low battery, programming error and motor malfunction alarms,

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

• positive pressure driven (continuous or pulsated).

The reservoir must be made of 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. For more information on the symptoms and treatment of overdose please refer to Section 4.9 of this document.

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

For subcutaneous infusion, Trepulmix 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 Trepulmix being used. During use a single reservoir (syringe) of undiluted Trepulmix can be administered up to 72 hours at 37°C. The subcutaneous infusion rate is calculated using the following formula:

*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng

To avoid calculation errors due to the complex formula please check the dose calculation tables below. For each medicinal product strength one dose calculation table is available.

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 Trepulmix Vial Strength, the infusion rate would be calculated as follows:

Example 2:

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

Table 1-1 provides guidance for subcutaneous infusion delivery rates of Trepulmix 1 mg/ml for patients of different body weights corresponding to doses of up to 42.5 ng/kg/min.

Table 1-1:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 1 mg/ml

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change every three days.

Table 1-2 provides guidance for subcutaneous infusion delivery rates of Trepulmix 2.5 mg/ml for patients of different body weights corresponding to doses of up to 42.5 ng/kg/min.

Table 1-2:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 2.5 mg/ml

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change every three days.

Table 1-3 provides guidance for subcutaneous infusion delivery rates of Trepulmix 5 mg/ml for patients of different body weights corresponding to doses of up to 80 ng/kg/min.

Table 1-3:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 5 mg/ml

The shaded areas indicate the highest infusion rate which is possible with a 3 ml syringe change every three days.

Table 1-4 provides guidance for subcutaneous infusion delivery rates of Trepulmix 10 mg/ml for patients of different body weights corresponding to doses of up to 155 ng/kg/min.

Table 1-4:

Infusion rate setting of subcutaneous pump (ml/h) for Trepulmix 10 mg/ml

Shaded areas indicate the highest infusion rate supported by a 3 ml syringe change every three days.

4.3. Contraindications

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

• Pulmonary veno-occlusive disease.

• Severe decompensated left heart failure.

• Severe hepatic impairment (Child-Pugh Class C).

• Active gastrointestinal ulcer, intracranial haemorrhage, gastrointestinal injury or other gastrointestinal bleeding.

• 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

• Severe arrhythmias

• Cerebrovascular events (e.g. transient ischaemic attack, stroke) within the last three months.

• Co-administration with other prostanoids

4.4. Special warnings and precautions for use

General therapy

The decision to initiate therapy with treprostinil should take into consideration the high probability that 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. 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).

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.

If a patient develops pulmonary oedema while on treprostinil, the possibility of an concomitant pulmonary veno-occlusive disease should be considered. The treatment should be stopped as pulmonary veno-occlusive disease is a contraindication for therapy with treprostinil (see section 4.3).

Caution is advised in situations where treprostinil may increase the risk of bleeding by inhibiting platelet aggregation (see section 4.5 and 4.8).

Withdrawal

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

Special populations

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).

Sodium content

Trepulmix 1 mg/ml solution for infusion

This medicinal product contains 36.8 mg sodium per 10 ml vial of 1 mg/ml, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 2.5 mg/ml solution for infusion

This medicinal product contains 37.3 mg sodium per 10 ml vial of 2.5 mg/ml, equivalent to 1.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 5 mg/ml solution for infusion

This medicinal product contains 39.1 mg sodium per 10 ml vial of 5 mg/ml, equivalent to 2.0% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Trepulmix 10 mg/ml solution for infusion

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

To be taken into consideration by patients on a controlled sodium diet.

Concomitant medicinal products

Concomitant administration of cytochrome P450 (CYP2C8) enzyme inhibitors (as gemfibrozil) may lead to increased exposure (both Cmax and AUC) to treprostinil. With an increased exposure there is a likelihood of a higher incidence of adverse events associated with the administration of treprostinil. Therefore, a dose reduction should be considered (see section 4.5).

Concomitant administration of CYP2C8 enzyme inducers (for example rifampicin) may result in a decreased exposure to treprostinil. At a reduced exposure, it is likely to have decreased clinical efficacy. Therefore, a higher dose of treprostinil is to be considered (see section 4.5).

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant administration with diuretics, antihypertensive agents, or other vasodilators

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

Concomitant administration with 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. The concomitant use of other platelet inhibitors should be avoided in patients taking anticoagulants.

Concomitant administration with cytochrome P450 (CYP2C8) enzyme inducers/inhibitors

Gemfibrozil and other CYP2C8 inhibitors

Pharmacokinetic studies in humans with oral treprostinil diolamine indicated that the concomitant administration of cytochrome P450 (CYP2C8) enzyme inhibitor gemfibrozil doubles the exposure (both Cmax and AUC) to treprostinil. In case a CYP2C8 inhibitor (e.g. gemfibrozil, trimethoprim and deferasirox) is added to or omitted from the patient's treatment after the titration phase, a dose adjustment of treprostinil has to be considered.

Rifampicin and other CYP2C8 inducers

Pharmacokinetic studies in humans with oral treprostinil diolamine indicated that the concomitant administration of CYP2C8 enzyme inducer rifampicin resulted in a reduced (by about 20%) exposure to treprostinil. In case rifampicin is added to or omitted from the patient's treatment after the titration phase, a dose adjustment of treprostinil has to be considered.

Also other CYP2C8 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's Wort) may lead to reduced exposure to treprostinil. In case a CYP2C8 inhibitor is added to or omitted from the patient's treatment after the titration phase, a dose adjustment of treprostinil has to be considered.

Concomitant administration with bosentan

In a pharmacokinetic study in humans, in which bosentan (250 mg/day) and treprostinil diolamine (oral dose of 2 mg/day) were administered concomitantly, no pharmacokinetic interaction between treprostinil and bosentan was observed.

Concomitant administration with sildenafil

In a pharmacokinetic study in humans, in which sildenafil (60 mg/day) and treprostinil diolamine (oral dose of 2 mg/day) were administered concomitantly, no pharmacokinetic interaction between treprostinil and sildenafil was observed.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of treprostinil in pregnant women. Animal studies are insufficient with respect to effects on pregnancy (see section 5.3). 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.

Breast-feeding

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

4.7. Effects on ability to drive and use machines

Treprostinil has minor influence on the ability to drive and use machines at the initiation of treatment or dose adjustments. They may be accompanied by undesirable effects such as symptomatic systemic hypotension or dizziness which may impair ability to drive and operate machinery.

4.8. Undesirable effects

Summary of safety profile

In addition to local effects resulting from the administration of treprostinil by subcutaneous infusion such as infusion site pain and infusion site reaction, adverse reactions with treprostinil are related to the pharmacological properties of prostacyclins.

Tabulated summary of adverse reactions

The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organ class. The incidence of the adverse reactions below are expressed according to the following categories: 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).

System organ class

Adverse reaction

Incidence

Nervous system disorders

Headache

Very common

Dizziness

Common

Eye disorders

Eyelid oedema

Uncommon

Cardiac disorders

Vasodilatation

Very common

Hypotension

Common

Gastrointestinal disorders

Diarrhoea

Very common

Nausea

Very common

Dyspepsia

Uncommon

Vomiting

Uncommon

Skin and subcutaneous tissue disorders

Rash

Common

Pruritus

Uncommon

Exanthema

Uncommon

Musculoskeletal, connective tissue disorders

Jaw pain

Very common

Myalgia, arthalgia

Common

Pain in extremities

Common

Back pain

Uncommon

General disorders and administration site conditions

Infusion site pain, infusion site reaction, bleeding or haematoma

Very common

Oedema

Common

Flushing

Common

Decreased appetite

Uncommon

Fatigue

Uncommon

Description of selected adverse reactions

Bleeding events

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 GI haemorrhage, rectal haemorrhage, gum haemorrhage and melaena) in controlled clinical trials in PAH.

Events Observed During Clinical Practice:

In addition to adverse reactions reported from clinical trials in PAH patients, the following events have been identified during post-approval use of treprostinil in other indications. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The following events were reported: infusion site infection, subcutaneous infusion site abscess formation, thrombocytopenia, and bone pain.

In addition, generalised rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.

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 Yellow Card Scheme

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

4.9. Overdose

Symptoms of overdose with treprostinil include flushing, headache, hypotension, nausea, vomiting, and diarrhoea. Patients experiencing symptoms of overdose should, after consultation with their physician, immediately reduce 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.