Treprostinil

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.

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

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

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.

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.

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. Treprostinil should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the foetus.

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

Women of child-bearing potential

Contraception is recommended during treprostinil treatment.

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.

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.