Trepulmix

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.

25 ng/kg/min. 625 ng/kg/min. 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. 2). 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

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, arthralgia 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 Infusion site abscess Common Infusion site infection Common Oedema Common Flushing Common Decreased appetite Uncommon Fatigue Uncommon Description of selected adverse reactions 11 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.

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.

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. 8 If a patient develops pulmonary oedema while on treprostinil, the possibility of a concomitant pulmonary veno-occlusive disease should be considered.

3). 8). 2). 2). 2). 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.

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. 5). 8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

9% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 0% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 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.

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 4 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.

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. 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).