Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: SciPharm Sàrl, 7, Fausermillen, L-6689, Mertert, Luxembourg
Trepulmix is indicated for the treatment of adult patients with WHO Functional Class (FC) III or IV and:
to improve exercise capacity.
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.
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.
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.
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.
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.
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.
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.
There is no relevant use of treprostinil in children and adolescents for the indication of CTEPH.
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:
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:
Subcutaneous Infusion Rate (ml/h) = Dose (ng/kg/min) x Weight (kg) x 0.00006* / Trepulmix Vial Strength (mg/ml)
* 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:
Subcutaneous Infusion Rate (ml/h) = 40 ng/kg/min x 65 kg x 0.00006 / 5 mg/ml = 0.031 ml/h
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.
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.
Unopened vial: 3 years.
After first opening: 30 days.
During use with continuous subcutaneous infusion: Chemical, physical and microbial in-use stability of a single container (syringe) of undiluted Trepulmix administered subcutaneously has been demonstrated for 72 h at 37°C.
This medicinal product does not require any special storage conditions.
For in-use storage times and conditions see section 6.3.
Trepulmix 1 mg/ml solution for infusion: 10 ml type I clear glass vial sealed with a rubber teflon- coated stopper and fitted with a yellow cap.
Trepulmix 2.5 mg/ml solution for infusion: 10 ml type I clear glass vial sealed with a rubber teflon-coated stopper and fitted with a blue cap.
Trepulmix, 5 mg/ml solution for infusion: 10 ml type I clear glass vial sealed with a rubber teflon-coated stopper and fitted with a green cap.
Trepulmix, 10 mg/ml solution for infusion: 10 ml type I clear glass vial sealed with a rubber teflon-coated stopper and fitted with a red cap.
Each carton contains one vial.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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