TABLE 2

Protocols for up-titration of therapies that target the prostacyclin pathway

PGI2 therapyInitiation protocolUp-titration protocolTarget dose and dosing frequencyDose adjustmentsAdditional comments
Epoprostenol
 Flolan [18]Short-term: 2 ng·kg−1·min−1; if this is not tolerated, a lower dose which is tolerated should be identified#
Long-term: 4 ng·kg−1·min−1 less than MTD identified during short-term dosing; if MTD ≤5 ng·kg−1·min−1, infusion should be started at 1 ng·kg−1·min−1
Increased by increments of 2 ng·kg−1·min−1 every 15 min or longer#Until maximum haemodynamic benefit or dose-limiting pharmacological effects#
Administered as continuous infusion#,
Increase: by 1–2 ng·kg−1·min−1 at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 min
Decrease: gradually in 2 ng·kg−1·min−1 decrements every 15 min or longer until dose-limiting effects resolve
Short-term dosing should be conducted in a hospital with adequate resuscitation equipment#
Abrupt withdrawal of Flolan or sudden large reductions in infusion rates should be avoided due to the risk of potential fatal rebound effects
Except in life-threatening situations, infusion rates should be adjusted only under the direction of a physician
 Veletri [19]Short-term:
2 ng·kg−1·min−1; if this is not tolerated, a lower dose which is tolerated should be identified#
Long-term: 4 ng·kg−1·min−1 less than MTD identified during short-term dosing; if MTD ≤5 ng·kg−1·min−1, infusion should be started at half the MTD
Increased by increments of 2 ng·kg−1·min−1 every 15 min or longer#Until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited#
Administered as continuous infusion#,
Increase: by 1–2 ng·kg−1·min−1 at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 min
Decrease: gradually in 2 ng·kg−1·min−1 decrements every 15 min or longer until dose-limiting effects resolve
Short-term dosing should be conducted in a hospital with adequate resuscitation equipment#
Abrupt withdrawal of Veletri or sudden large reductions in infusion rates should be avoided due to the risk of potential fatal rebound effects
Except in life-threatening situations, infusion rates should be adjusted only under the direction of a physician
Treprostinil
 Remodulin i.v./s.c. [6]1.25 ng·kg−1·min−1 for patients new to PGI2 infusion therapy; reduce to 0.625 ng·kg−1·min−1 if 1.25 ng·kg−1·min−1 is not toleratedThe prescribing information suggests increments of 1.25 ng·kg−1·min−1 per week for the first 4 weeks of treatment and increments of 2.5 ng·kg−1·min−1 per week after 4 weeks of up-titration. In clinical practice, the dose is usually increased more quickly, aiming to reach 20 ng·kg−1·min−1 after 4 weeks [29]Based on clinical response
Administered as a continuous infusion
NAAvoid abrupt cessation
In the case of mild to moderate hepatic insufficiency, decrease initial dose to 0.625 ng·kg−1·min−1
If transitioning from i.v. epoprostenol, the dose should be increased while simultaneously reducing the dose of i.v. epoprostenol. The transition to Remodulin should take place in the hospital with constant observation of response
 Tyvaso [8]3 breaths (18 µg) per treatment session; if 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths as toleratedIncrease by an additional 3 breaths at 1–2-week intervals9 breaths (54 µg) per treatment session, 4 times dailyNATitrate slowly in patients with hepatic or renal insufficiency
 Orenitram [11]0.25 mg twice or 0.125 mg three times dailyIncrease by 0.25 or 0.5 mg twice daily or 0.125 mg three times daily, not more than every 3–4 days as toleratedMTD is determined by tolerability; increase to highest MTD
Administered twice or three times daily
If intolerable pharmacological effects occur, decrease the dose in increments of 0.25 mgIf transitioning from i.v./s.c. Remodulin, the dose should be increased while simultaneously decreasing the i.v./s.c. infusion rate
In the case of mild hepatic impairment, initiate at 0.125 mg twice daily, increase at 0.125 mg twice daily every 3–4 days
Avoid abrupt discontinuation
Iloprost
 Ilomedin [7]0.5 ng·kg−1·min−1 for 30 minIncrease by 0.5 ng·kg−1·min−1 in 30-min intervals up to 2.0 ng·kg−1·min−1MTD within the range of 0.5–2.0 ng·kg−1·min−1
Administered as an i.v. infusion over 6 h daily
If undesirable side-effects occur, the infusion rate should be reduced until the tolerable dose is foundShould only be used under strict monitoring in hospitals or outpatient clinics with adequate facilities
 Ventavis [9]2.5 µg per treatment sessionIncrease to 5 µg if initial dose is well toleratedAdministered 6–9 times daily, depending on individual need and tolerability, up to 5 µg per treatment sessionIn cases of poor tolerability of the 5 µg dose, the dose should be reduced to 2.5 µg per treatment sessionIn patients with hepatic impairment, special caution should be exercised during initial dose titration
Beraprost
 Dorner [15]20 µg three times dailyThe dosage may be increased gradually according to symptomsMaximum daily
dose should not exceed 9 tablets (180 µg)
If the dose is increased, it may be taken 3–4 times daily
NA
Selexipag
 Uptravi [12]200 µg twice daily, 12 h apartIncreased in increments of 200 µg twice daily, at weekly intervalsMTD (can range from 200 to 1600 µg twice daily)
Administered twice daily
If the patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous dose levelAt the beginning of treatment, and at each up-titration step, it is recommended to take the first dose in the evening
If treatment is missed for 3 days or more, Uptravi should be re-started at a lower dose and then up-titrated
Withdrawal of Uptravi should be done gradually, while an alternative therapy is introduced
  • PGI2: prostaglandin I2 (prostacyclin); MTD: maximum tolerated dose; NA: not available. #: short term; : long term.