TREPULMIX Solution for infusion Ref.[9389] Active ingredients: Treprostinil

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 1mg/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 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 C max 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).

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 C_max 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 (60mg/day) and treprostinil diolamine (oral dose of 2 mg/day) were administered concomitantly, no pharmacokinetic interaction between treprostinil and sildenafil was observed.

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.

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.

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).

Nervous system disorders

Very common: Headache

Common: Dizziness

Eye disorders

Uncommon: Eyelid oedema

Cardiac disorders

Very common: Vasodilatation

Common: Hypotension

Gastrointestinal disorders

Very common: Diarrhoea, Nausea

Uncommon: Dyspepsia, Vomiting

Skin and subcutaneous tissue disorders Rash Common

Uncommon: Pruritus, Exanthema

Musculoskeletal, connective tissue disorders

Very common: Jaw pain

Common: Myalgia, arthalgia, Pain in extremities

Uncommon: Back pain

General disorders and administration site conditions

Very common: Infusion site pain, infusion site reaction, bleeding or haematoma

Common: Oedema, Flushing

Uncommon: Decreased appetite, Fatigue

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 the national reporting system listed in Appendix V.*

This medicinal product must not be mixed with other medicinal products.